Substituted Pyrrolidine Amides II

ABSTRACT

which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

This application claims foreign priority benefit of European ApplicationNo. 17 208 180.4, filed Dec. 18, 2017, the disclosure of which patentapplication is incorporated herein by reference

The invention relates to compounds according to general formula (I)

which act as modulators of the glucocorticoid receptor and can be usedin the treatment and/or prophylaxis of disorders which are at leastpartially mediated by the glucocorticoid receptor.

Glucocorticoids (GC) exert strong anti-inflammatory, immunosuppressiveand disease-modifying therapeutic effects mediated by the glucocorticoidreceptor (GR). They have been widely used to treat inflammatory andimmune diseases for decades and still represent the most effectivetherapy in those conditions. However, chronic GC treatment ofinflammatory diseases such as asthma, rheumatoid arthritis, inflammatorybowel disease, chronic obstructive pulmonary disease, acute respiratorydistress syndrome, cystic fibrosis, osteoarthritis, polymyalgiarheumatica and giant cell arteritis is hampered by GC-associated adverseeffects. These undesired side effects include insulin resistance,diabetes, hypertension, glaucoma, depression, osteoporosis, adrenalsuppression and muscle wasting with osteoporosis and diabetes being themost severe ones from the physician's point of view (Hapgood JP. et al.,Pharmacol Ther. 2016 September; 165: 93-113; Buttgereit F. el al, ClinExp Rheumatol. 2015 July-August, 33(4 Suppl 92):S29-33; Hartmann K. etal, Physiol Rev. 2016 April; 96(2):409-47).

One example of an oral glucocorticoid is prednisone which is frequentlyprescribed for the treatment of several inflammatory disorders (DeBosscher K et al., Trends Pharmacol Sci. 2016 January; 37(1):4-16;Buttgereit F. et al., JAMA. 2016; 315(22):2442-2458). As GC causeadrenal suppression, prednisolone withdrawal symptoms can be severe ifthe drug is discontinued abruptly when all the signs of the disease havedisappeared. Thus gradual GC tapering to physiological doses isfrequently part of treatment protocols to reduce the risk of relapse andother withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol.2013 Aug. 15; 9(1):30). Therefore, there is high medical need for novelpotent anti-inflammatory drugs with less adverse effects.

Recent research has focused on the development of partial agonists orselective glucocorticoid receptor modulators which activate the pathwaysfor the inhibition of inflammation but avoid targeting the pathways thatlead to the GC-associated adverse effects. Most of these effects havebeen demonstrated to be mediated by different GR-dependent genomicmechanisms termed transactivation and transrepression. Theanti-inflammatory actions of GC are mainly attributable to thetransrepression of inflammatory genes while certain side effects arepredominantly mediated via transactivation of several genes. Accordingto the nature of a ligand the GR can be selectively modulated in aspecific conformation which favors transrepression over transactivationresulting in an improved therapeutic benefit (De Bosscher K et al.,Trends Pharmacol Sci. 2016 January; 37(1):4-16). The concept of suchdissociating ligands was already defined about two decades ago andseveral compounds have been identified and were evaluated in preclinicaland clinical testing but none of them has as yet been approved forclinical use.

Compounds which are active as modulators of the glucocorticoid receptorare also known e.g. from WO 2007/122165, WO 2008/076048 and WO2008/043789, WO 2009/035067, WO 2009/142571, WO 2016/046260, and WO2017/034006.

It was an object of the invention to provide novel compounds which aremodulators of the glucocorticoid receptor and which preferably haveadvantages over the compounds of the prior art. The novel compoundsshould in particular be suitable for use in the treatment and/orprophylaxis of disorders or diseases which are at least partiallymediated by the glucocorticoid receptor.

This object has been achieved by the subject-matter as described herein.

It was surprisingly found that the compounds according to the inventionare highly potent modulators of the glucocorticoid receptor.

The invention relates to a compound according to general formula (I),

-   wherein-   R₁ represents —C₁₋₁₀-alkyl; —C₃₋₁₀-cycloalkyl;    —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; 3 to 7 membered heterocycloalkyl;    —C₁₋₆-alkylene-(3 to 7 membered heterocycloalkyl); aryl;    —C₁₋₆-alkylene-aryl; 5 or 6-membered heteroaryl; or    —C₁₋₆-alkylene-(5 or 6-membered heteroaryl);-   R₂ represents —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;    —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cyclo-alkyl; —C(═O)-(3 to 7 membered    heterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7 membered    heterocycloalkyl); —C(═O)-aryl; —C(═O)—C₁₋₆-alkylene-aryl; —C(═O)-(5    or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or 6-membered    heteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl; —S(═O)₁₋₂—C₃₋₁₀-cycloalkyl;    —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂-(3 to 7 membered    heterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3 to 7 membered    heterocycloalkyl); —S(═O)₁₋₂-aryl; —S(═O)₁₋₂—C₁₋₆-alkylene-aryl;    —S(═O)₁₋₂-(5 or 6-membered heteroaryl); or    —S(═O)₁₋₂—C₁₋₆-alkylene-(5 or 6-membered heteroaryl);-   R₃ represents —C₁₋₁₀-alkyl; —C₃₋₁₀-cycloalkyl;    —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl; —C₁₋₆-alkylene-aryl;    —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;    —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-aryl;    —C(═O)—C₁₋₆-alkylene-aryl; —S(═O)₁₋₂—C₁₋₁₀-alkyl;    —S(═O)₁₋₂—C₃₋₁₀-cycloalkyl;    —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂-aryl; or    —S(═O)₁₋₂—C₁₋₆-alkylene-aryl;-   R₄ represents —H; —F; —Cl; —Br; —I; —CN; —CF₃; —CF₂H; —CFH₂ or    cyclopropyl;-   X represents N or CR₅; wherein R₅ represents —H; —F; —Cl; —Br; —I;    —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl;-   Y represents N or CR₆; wherein R₆ represents —H; —F; —Cl; —Br; —I;    —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl;-   Z represents N or CR₇; wherein R₇ represents —H; —F; —Cl; —Br; —I;    —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl;    wherein —C₁₋₁₀-alkyl, —C₁₋₄-alkyl and —C₁₋₆-alkylene- in each case    independently from one another is linear or branched, saturated or    unsaturated;    wherein —C₁₋₁₀-alkyl, —C₁₋₄-alkyl, —C₁₋₆-alkylene-,    —C₃₋₁₀-cycloalkyl and 3 to 7 membered hetero-cycloalkyl in each case    independently from one another are unsubstituted or mono- or    polysubstituted with one or more substituents selected from —F; —Cl;    —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;    —C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂;    —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃;    —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;    —O—C(═O)—C₁₋₆-alkyl; —O—C(═O)—O—C₁₋₆-alkyl; —O—(CO)—NH(C₁₋₆-alkyl);    —O—C(═O)—N(C₁₋₆-alkyl)₂; —O—S(═O)₂—NH₂; —O—S(═O)₂—NH(C₁₋₆-alkyl);    —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂; —NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂;    —NH—C(═O)—C₁₋₆-alkyl; —NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂;    —NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;    —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl;    —N(C₁₋₆-alkyl)-C(═O)—NH₂; —N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);    —N(C₁₋₆-alkyl)-C(═O)—N(C(C₁₋₆-alkyl)₂; —NH—S(═O)₂OH;    NH—S(═O)₂—C₁₋₆-alkyl; —NH—S(═O)₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂;    —NH—S(═O)₂—NH(C₁₋₆-alkyl); —NH—S(═O)₂N(C₁₋₆-alkyl)₂;    —N(C₁₋₆-alkyl)-S(═O)₂—OH; —N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;    —N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—NH₂;    —N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);    —N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;    —S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—OH;    —S(═O)₂—O—C₁₋₆-alkyl; .S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);    —S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl; 3 to 6-membered    heterocycloalkyl; phenyl; 5 or 6-membered heteroaryl;    —O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl);    —O-phenyl; —O-(5 or 6-membered heteroaryl); —C(═O)—C₃₋₆-cycloalkyl;    —C(═O)-(3 to 6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5    or 6-membered heteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to    6-membered heterocycloalkyl); —S(═O)₂-phenyl or —S(═O)₂-(5 or    6-membered heteroaryl);    wherein aryl and 5 or 6-membered heteroaryl in each case    independently from one another are unsubstituted or mono- or    polysubstituted with one or more substituents selected from —F; —Cl;    —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;    —C₁₋₄-alkylene-CF₃; —C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂;    —C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH);    —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O;    —OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;    —O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;    —NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;    —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;    —NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;    —N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);    —N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl; —SCF₃;    —S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—NH₂;    —S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl;    —C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl;    —C₁₋₄-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or    6-membered heteroaryl;    in the form of the free compound or a physiologically acceptable    salt thereof.

In a preferred embodiment, the compound according to the invention ispresent in form of the free compound. For the purpose of specification,“free compound” preferably means that the compound according to theinvention is not present in form of a salt. Methods to determine whethera chemical substance is present as the free compound or as a salt areknown to the skilled artisan such as ¹⁴N or ¹⁵N solid state NMR, x-raydiffraction, x-ray powder diffraction, IR, Raman, XPS. ¹H-NMR recordedin solution may also be used to consider the presence of protonation.

In another preferred embodiment, the compound according to the inventionis present in form of a physiologically acceptable salt. For thepurposes of this specification, the term “physiologically acceptablesalt” preferably refers to a salt obtained from a compound according tothe invention and a physiologically acceptable acid or base.

According to the invention, the compound according to the invention maybe present in any possible form including solvates, cocrystals andpolymorphs. For the purposes of this specification, the term “solvate”preferably refers to an adduct of (i) a compound according to theinvention and/or a physiologically acceptable salt thereof with (ii)distinct molecular equivalents of one or more solvents.

Further, the compound according to the invention may be present in formof the racemate, enantiomers, diastereomers, tautomers or any mixturesthereof.

The invention also includes isotopic isomers of a compound of theinvention, wherein at least one atom of the compound is replaced by anisotope of the respective atom which is different from the naturallypredominantly occurring isotope, as well as any mixtures of isotopicisomers of such a compound. Preferred isotopes are ²H (deuterium), ³H(tritium), ¹³C and ¹⁴C. Isotopic isomers of a compound of the inventioncan generally be prepared by conventional procedures known to a personskilled in the art.

According to the invention, the terms “—C₁₋₁₀-alkyl”, “—C₁₋₈-alkyl”,“—C₁₋₆-alkyl” and “—C₁₋₄-alkyl” preferably mean acyclic saturated orunsaturated aliphatic (i.e. non-aromatic) hydrocarbon residues, whichcan be linear (i.e. unbranched) or branched and which can beunsubstituted or mono- or polysubstituted (e.g. di- or trisubstituted),and which contain 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), 1 to 8(i.e. 1, 2, 3, 4, 5, 6, 7 or 8), 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1to 4 (i.e. 1, 2, 3 or 4) carbon atoms, respectively. In a preferredembodiment, —C₁₋₁₀-alkyl, —C₁₋₈-alkyl, —C₁₋₆-alkyl and —C₁₋₄-alkyl aresaturated. In another preferred embodiment, —C₁₋₁₀-alkyl, —C₁₋₈-alkyl,—C₁₋₆-alkyl and —C₁₋₄-alkyl are not saturated. According to thisembodiment, —C₁₋₁₀-alkyl, —C₁₋₈-alkyl, —C₁₋₆-alkyl and —C₁₋₄-alkylcomprise at least one C—C double bond (a C═C-bond) or at least one C—Ctriple bond (a C≡C-bond). In still another preferred embodiment,—C₁₋₁₀-alkyl, —C₁₋₈-alkyl, —C₁₋₆-alkyl and —C₁₋₄-alkyl are (i) saturatedor (ii) not saturated, wherein —C₁₋₁₀-alkyl, —C₁₋₆-alkyl, —C₁₋₆-alkyland —C₁₋₄-alkyl comprise at least one, preferably one, C—C triple bond(a C≡C-bond).

Preferred —C₁₋₁₀-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl,n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl,2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl,3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

Preferred —C₁₋₈-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl,2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl,3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl,3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl,n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (—CH₂CH═CH₂,—CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl,2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl,3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl,3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl,2,2-dimethylpropyl, n-hexyl, n-heptyl and n-octyl.

Preferred —C₁₋₆-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl,2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl,2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl,3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferablymethyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂—CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl,2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl,3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl. Particularly preferred—C₁₋₆-alkyl groups are selected from C₁₋₄-alkyl groups.

Preferred —C₁₋₄-alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), n-butyl, 1-butynyl, 2-butynyl,1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and3-methylbut-1-ynyl.

Further according to the invention, the terms “—C₁₋₆-alkylene-”;“—C₁₋₄-alkylene-” and “—C₁₋₂-alkylene-” relate to a linear or branched,preferably linear, and preferably saturated aliphatic residues which arepreferably selected from the group consisting of methylene (—CH₂—),ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂— or —C(CH₃)₂—), butylene(—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—) and hexylene(—CH₂CH₂CH₂CH₂CH₂CH₂—); more preferably methylene (—CH₂—) and ethylene(—CH₂CH₂—) and most preferably methylene (—CH₂—). Preferably,—C₁₋₆-alkylene- is selected from —C₁₋₄-alkylene-, more preferably from—C₁₋₂-alkylene-.

Still further according to the invention, the terms “—C₃₋₁₀-cycloalkyl”and “—C₃₋₆-cycloalkyl” preferably mean cyclic aliphatic hydrocarbonscontaining 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6carbon atoms, respectively, wherein the hydrocarbons in each case can besaturated or unsaturated (but not aromatic), unsubstituted or mono- orpolysubstituted.

Preferably, —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl are saturated. The—C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl can be bound to the respectivesuperordinate general structure via any desired and possible ring memberof the cycloalkyl group. The —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkylgroups can also be condensed with further saturated, (partially)unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems,i.e. with cycloalkyl, heterocyclyl, aryl or heteroaryl residues, whichin each case can in turn be unsubstituted or mono- or polysubstituted.Further, —C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl can be singly ormultiply bridged such as, for example, in the case of adamantyl,bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. However, preferably,—C₃₋₁₀-cycloalkyl and —C₃₋₆-cycloalkyl are neither condensed withfurther ring systems nor bridged. More preferably, —C₃₋₁₀-cycloalkyl and—C₃₋₆-cycloalkyl are neither condensed with further ring systems norbridged and are saturated. Preferred —C₃₋₁₀-cycloalkyl groups areselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecyl, adamantly, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl andbicyclo[2.2.2]octyl. Particularly preferred —C₃₋₁₀-cycloalkyl groups areselected from —C₃₋₆-cycloalkyl groups.

Preferred —C₃₋₆-cycloalkyl groups are selected from the group consistingof cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl andcyclohexenyl. Particularly preferred —C₃-6-cycloalkyl groups areselected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, most preferably cyclopropyl.

According to the invention, the terms “3 to 7-membered heterocycloalkyl”and “3 to 6-membered heterocycloalkyl” preferably meanheterocycloaliphatic saturated or unsaturated (but not aromatic)residues having 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members and 3 to 6,i.e. 3, 4, 5 or 6 ring members, respectively, wherein in each case atleast one, if appropriate also two or three carbon atoms are replaced bya heteroatom or a heteroatom group each selected independently of oneanother from the group consisting of O, S, S(═O), S(═O)₂, N, NH andN(C₁₋₄-alkyl) such as N(CH₃), wherein the carbon atoms of the ring canbe unsubstituted or mono- or polysubstituted.

Preferably, 3 to 7-membered heterocycloalkyl and 3 to 6-memberedheterocycloalkyl are saturated. The 3 to 7-membered heterocycloalkyl andthe 3 to 6-membered heterocycloalkyl groups can also be condensed withfurther saturated or (partially) unsaturated cycloalkyl or heterocyclyl,aromatic or heteroaromatic ring systems. However, more preferably, 3 to7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are notcondensed with further ring systems. Still more preferably, 3 to7-membered heterocycloalkyl and 3 to 6-membered heterocycloalkyl are notcondensed with further ring systems and are saturated. The 3 to7-membered heterocycloalkyl and the 3 to 6-membered heterocycloalkylgroup can be bound to the superordinate general structure via anydesired and possible ring member of the heterocycloaliphatic residue ifnot indicated otherwise. In a preferred embodiment, 3 to 7-memberedheterocycloalkyl and 3 to 6-membered heterocycloalkyl are bound to thesuperordinate general structure via a carbon atom.

Preferred 3 to 7-membered heterocycloalkyl groups are selected from thegroup consisting of azepanyl, dioxepanyl, oxazepanyl, diazepanyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl,thiomorpholinyl, tetrahydropyranyl, oxetanyl, oxiranyl,tetrahydrofuranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl,morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl,dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl,dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl;tetrahydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl,dihydroindolinyl, dihydroisoindolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl and tetrahydroindolinyl. Particularly preferred3 to 7-membered heterocycloalkyl groups are selected from 3 to6-membered heterocycloalkyl groups.

Preferred 3 to 6-membered heterocycloalkyl groups are selected from thegroup consisting of tetrahydropyranyl, oxetanyl, oxiranyl,tetrahydrofuranyl, thiazolidinyl, tetrahydrothiophenyl,tetrahydropyridinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl,4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl,dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl,dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl,oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl,tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl andtetrahydroindolinyl. Particularly preferred 3 to 6-memberedheterocycloalkyl groups are selected from the group consisting oftetrahydropyranyl, oxetanyl, oxiranyl, and tetrahydrofuranyl.

According to the invention, the term “aryl” preferably means aromatichydrocarbons having 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ringmembers, preferably having 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members,including phenyls and naphthyls. Each aryl residue can be unsubstitutedor mono- or polysubstituted. The aryl can be bound to the superordinategeneral structure via any desired and possible ring member of the arylresidue. The aryl residues can also be condensed with further saturatedor (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic orheteroaromatic ring systems, which can in turn be unsubstituted or mono-or polysubstituted. In a preferred embodiment, aryl is condensed with afurther ring system. Examples of condensed aryl residues are2H-benzo[b][1,4]oxazin-3(4H)-onyl, 1H-benzo[d]imidazolyl,2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, isochroman,1,3-dihydroisobenzofuranyl, benzodioxolanyl and benzodioxanyl.

Preferably, aryl is selected from the group consisting of phenyl,1H-benzo[d]imidazolyl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl,2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, isochroman,1,3-dihydroisobenzofuranyl, 1-naphthyl, 2-naphthyl, fluorenyl andanthracenyl, each of which can be respectively unsubstituted or mono- orpolysubstituted. In another preferred embodiment, aryl is not condensedwith any further ring system. A particularly preferred aryl is phenyl,unsubstituted or mono- or polysubstituted.

According to the invention, the term “5- to 6-membered heteroaryl”preferably means a 5 or 6-membered cyclic aromatic residue containing atleast 1, if appropriate also 2, 3, 4 or 5 heteroatoms, wherein theheteroatoms are each selected independently of one another from thegroup S, N and O and the heteroaryl residue can be unsubstituted ormono- or polysubstituted, if not indicated otherwise. In the case ofsubstitution on the heteroaryl, the substituents can be the same ordifferent and be in any desired and possible position of the heteroaryl.The binding to the superordinate general structure can be carried outvia any desired and possible ring member of the heteroaryl residue ifnot indicated otherwise. Preferably, the 5- to 6-membered heteroaryl isbound to the suprordinate general structure via a carbon atom of theheterocycle. The heteroaryl can also be part of a bi- or polycyclicsystem having up to 14 ring members, wherein the ring system can beformed with further saturated or (partially) unsaturated cycloalkyl orheterocycloalkyl, aromatic or heteroaromatic ring systems, which can inturn be unsubstituted or mono- or polysubstituted, if not indicatedotherwise. In a preferred embodiment, the 5- to 6-membered heteroaryl ispart of a bi- or polycyclic, preferably bicyclic, system. In anotherpreferred embodiment, the 5- to 6-membered heteroaryl is not part of abi- or polycyclic system.

Preferably, the 5- to 6-membered heteroaryl is selected from the groupconsisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridone(pyridinone), pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl,thienyl (thiophenyl), triazolyl, thiadiazolyl,4,5,6,7-tetrahydro-2H-indazolyl,2,4,5,6-tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl,benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl,benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl,quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl,imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl,naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl,phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl.Particularly preferred 5- to 6-membered heteroaryl are selected from thegroup consisting of pyridyl (i.e. 2-pyridyl, 3-pyridyl, 4-pyridyl). Aspyridones can be regarded as pyridines that are substituted with ═O, forthe purpose of the specification the definition of pyridines that mayoptionally be substituted with ═O covers pyridones.

The compounds according to the invention are defined by substituents,for example by R₁, R₂, R₃ and R₄ (1^(st) generation substituents) whichmay optionally be for their part themselves be substituted (2^(nd)generation substituents). Depending on the definition, thesesubstituents of the substituents can optionally be for their partresubstituted (3^(rd) generation substituents). If, for example,R₁═—C₁₋₁₀-alkyl (1^(st) generation substituent), then the —C₁₋₁₀-alkylcan for its part be substituted, for example with a —NH(C₁₋₆-alkyl)(2^(nd) generation substituent). This produces the functional groupR₁═(—C₁₋₁₀-alkyl-NH—C₁₋₆-alkyl). The —NH—C₁₋₆-alkyl can then for itspart be resubstituted, for example with —Cl (3^(rd) generationsubstituent). Overall, this produces the functional groupR₁═—C₁₋₁₀-alkyl-NH—C₁₋₆-alkyl, wherein the —C₁₋₆-alkyl of the—NH—C₁₋₆-alkyl is substituted by —Cl.

However, in a preferred embodiment, the 3^(rd) generation substituentsmay not be resubstituted, i.e. there are then no 4^(th) generationsubstituents. More preferably, the 2^(nd) generation substituents maynot be resubstituted, i.e. there are no 3^(rd) generation substituents.

If a residue occurs multiply within a molecule, then this residue canhave respectively different meanings for various substituents: if, forexample, both R₂ and R₃ denote —C₁₋₆-alkyl, then —C₁₋₆-alkyl can e.g.represent ethyl for R₂ and can represent methyl for R₃.

In connection with the terms “—C₁₋₁₀-alkyl”, “—C₁₋₆-alkyl”,“—C₁₋₄-alkyl”, “—C₃₋₁₀-cycloalkyl”, “—C₃₋₆-cycloalkyl”, “3 to 7 memberedheterocycloalkyl”, “3 to 6-membered heterocycloalkyl”,“—C₁₋₆-alkylene-”, “—C₁₋₄-alkylene-” and “—C₁₋₂-alkylene-”, the term“substituted” refers in the sense of the invention, with respect to thecorresponding residues or groups, to the single substitution(monosubstitution) or multiple substitution (polysubstitution), e.g.disubstitution or trisubstitution; more preferably to monosubstitutionor disubstitution; of one or more hydrogen atoms each independently ofone another by at least one substituent. In case of a multiplesubstitution, i.e. in case of polysubstituted residues, such as di- ortrisubstituted residues, these residues may be polysubstituted either ondifferent or on the same atoms, for example trisubstituted on the samecarbon atom, as in the case of —CF₃, —CH₂CF₃ or disubstituted as in thecase of 1,1-difluorocyclohexyl, or at various points, as in the case of—CH(OH)—CH═CH—CHCl₂ or 1-chloro-3-fluorocyclohexyl. The multiplesubstitution can be carried out using the same or using differentsubstituents.

In relation to the terms “aryl”, “phenyl”, “heteroaryl” and “5- to6-membered heteroaryl”, the term “substituted” refers in the sense ofthis invention to the single substitution (monosubstitution) or multiplesubstitution (polysubstitution), e.g. disubstitution or trisubstitution,of one or more hydrogen atoms each independently of one another by atleast one substituent. The multiple substitution can be carried outusing the same or using different substituents.

According to the invention, preferably —C₁₋₁₀-alkyl-, —C₁₋₆-alkyl,—C₁₋₄-alkyl, —C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 memberedheterocycloalkyl, 3 to 6-membered heterocycloalkyl, —C₁₋₆-alkylene-,—C₁₋₄-alkylene- and —C₁₋₂-alkylene- in each case independently from oneanother are unsubstituted or mono- or polysubstituted with one or moresubstituents selected from —F; —Cl; —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃;—CF₂H; —CFH₂; —CF₂Cl; —CFCl₂; —C(═O)—C₁₋₆-alkyl; —C(═O)—OH;—C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂;—O—C₁₋₆-alkyl; —O—C(═O)—C₁₋₆-alkyl; —O—C(═O)—O—C₁₋₆-alkyl;—O—(CO)—NH(C₁₋₆-alkyl); —O—C(═O)—N(C₁₋₆-alkyl)₂; —O—S(═O)₂—NH₂;—O—S(═O)₂—NH(C₁₋₆-alkyl); —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂; —NH—C(═O)—NH(C₁₋₆-alkyl);—NH—C(═O)—N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—NH₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂OH;—NH—S(═O)₂—C₁₋₆-alkyl; —NH—S(═O)₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂;—NH—S(═O)₂—NH(C₁₋₆-alkyl); —NH—S(═O)₂N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-S(═O)₂—OH; —N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-S(═O)₂—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—NH₂;—N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—OH;—S(═O)₂—O—C₁₋₆-alkyl; —S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);—S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl; 5 or 6-membered heteroaryl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl;—O-(5 or 6-membered heteroaryl); —C(═O)—C₃₋₆-cycloalkyl; C(═O)-(3 to6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to 6-memberedheterocycloalkyl); —S(═O)₂-phenyl and —S(═O)₂-(5 or 6-memberedheteroaryl).

Preferred substituents of —C₁₋₁₀-alkyl, —C₁₋₆-alkyl, —C₁₋₄-alkyl,—C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3to 6-membered heterocycloalkyl, —C₁₋₆-alkylene- and —C₁₋₄-alkylene- areselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—C₁₋₆-alkyl; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂; —S—C₁₋₆-alkyl;—S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —C₃₋₆-cycloalkyl; 3 to 6-memberedhetero-cycloalkyl; phenyl and 5 or 6-membered heteroaryl; andparticularly preferably —F, —CN, —CH₃, —CH₂CH₃, —CF₃; —CF₂H; —CFH₂;—C(═O)—NH₂; —C(═O)—NH(CH₃); —C(═O)—N(CH₃)₂; —OH, —NH₂, —OCH₃, —SCH₃,—S(═O)₂(CH₃), —S(═O)(CH₃), —N(CH₃)₂, cyclopropyl and oxetanyl. Accordingto this embodiment, —C₁₋₁₀-alkyl, —C₁₋₆-alkyl, —C₁₋₄-alkyl,—C₃₋₁₀-cycloalkyl, —C₃₋₆-cycloalkyl, 3 to 7 membered heterocycloalkyl, 3to 6-membered heterocycloalkyl are preferably each independently fromone another unsubstituted, mono- di- or trisubstituted, more preferablyunsubstituted or monosubstituted or disubstituted with a substituentselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl);—C(═O)—N(C₁₋₆-alkyl)₂; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—C₁₋₆-alkyl; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂; —S—C₁₋₆-alkyl;—S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl and 5 or 6-membered heteroaryl. Preferably,—C₁₋₆-alkylene-groups and —C₁₋₄-alkylene-groups are unsubstituted.

According to the invention, preferably aryl, phenyl and 5 or 6-memberedheteroaryl in each case independently from one another are unsubstitutedor mono- or polysubstituted with one or more substituents selected from—F; —Cl; —Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C₁₋₄-alkylene-CF₃; C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH);—C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; ═O; —OH;—OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;—NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl; —SCF₃;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—NH₂;—S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl;—C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl;—C₁₋₄-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or6-membered heteroaryl.

Preferred substituents of aryl, phenyl and 5 or 6-membered heteroarylare selected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C₁₋₄-alkylene-CF₃;—C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂; —OH; —OCF₃; —OCF₂H; —OCFH₂;—O—C₁₋₆-alkyl; —O—C₃₋₆-cycloalkyl and —C₃₋₆-cycloalkyl; and particularlypreferably of —F; —Cl; —Br; —CN; —CH₃; —CH₂CH₃; —CF₃; —CF₂H; —CFH₂;—CH₂—CF₃; ═O; —OH; —OCF₃; —OCF₂H; —OCFH₂; —O—CH₃; —O-cyclopropyl andcyclopropyl. According to this embodiment, aryl, phenyl and 5 or6-membered heteroaryl are preferably each independently from one anotherunsubstituted, mono- di- or trisubstituted, more preferablyunsubstituted or monosubstituted or disubstituted with a substituentselected from the group consisting of —F; —Cl; —Br; —I; —CN;—C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —C₁₋₄-alkylene-CF₃;—C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂; ═O; —OH; —OCF₃; —OCF₂H;—OCFH₂; —O—C₁₋₆-alkyl; —O—C₃₋₆-cycloalkyl and —C₃₋₆-cycloalkyl. Aparticularly preferred substituted 5 or 6-membered heteroaryl isN-methyl-2-oxo-pyridyl.

In a preferred embodiment, the compound according to the invention has astereochemistry according to general formula (II), (III), (IV) or (V)

In a preferred embodiment, the compound according to the invention has astereochemistry according to general formula (II) or (III), such thatthe residues —R₁ and —NH—R₂ on the pyrrolidone ring are oriented trans.Preferably, the compound according to the invention has astereochemistry according to general formula (II). Preferably, thecompound according to the invention has a stereochemistry according togeneral formula (III). The stereochemistry according to general formula(II) is particularly preferred.

In another preferred embodiment, the compound according to the inventionhas a stereochemistry according to general formula (IV) or (V), suchthat the residues —R₁ and —NH—R₂ on the pyrrolidone ring are orientedcis. Preferably, the compound according to the invention has astereochemistry according to general formula (IV). Preferably, thecompound according to the invention has a stereochemistry according togeneral formula (V).

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), R₁ represents —C₁₋₁₀-alkyl;—C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; 3 to 7 memberedheterocycloalkyl; —C₁₋₆-alkylene-(3 to 7 membered heterocycloalkyl);aryl; —C₁₋₆-alkylene-aryl; 5 or 6-membered heteroaryl; or—C₁₋₆-alkylene-(5 or 6-membered heteroaryl).

In a preferred embodiment, R₁ represents —C₃₋₁₀-cycloalkyl;—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl; or 5 or 6-membered heteroaryl.

In particularly preferred embodiments, R₁ represents

-   (i) cyclopropyl, unsubstituted;-   (ii) —CH₂-cyclopropyl, unsubstituted;-   (iii) phenyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, cyclopropyl, and —OCH₃,    wherein phenyl is optionally annealed to a dioxolane ring by a    substituent —O—CH₂CH₂—O—; or-   (iv) pyridyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), R₂ represents —C(═O)—C₁₋₁₀-alkyl;—C(═O)—C₃₋₁₀-cycloalkyl; —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7membered heterocycloalkyl); —C(═O)-aryl; —C(═O)—C₁₋₆-alkylene-aryl;—C(═O)-(5 or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or6-membered heteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl;—S(═O)₁₋₂—C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂-(3 to 7 membered heterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3to 7 membered heterocycloalkyl); —S(═O)₁₋₂-aryl;—S(═O)₁₋₂—C₁₋₆-alkylene-aryl; —S(═O)₁₋₂-(5 or 6-membered heteroaryl); or—S(═O)₁₋₂—C₁₋₆-alkylene-(5 or 6-membered heteroaryl).

In a preferred embodiment, R₂ represents —C(═O)—C₁₋₁₀-alkyl;—C(═O)—C₃₋₁₀-cycloalkyl; —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—C₁₋₁₀-alkyl; —S(═O)₂—C₃₋₁₀-cycloalkyl;—S(═O)₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl or —S(═O)₂-(5 or 6-memberedheteroaryl).

In particularly preferred embodiments, R₂ represents

-   (i) —C(═O)—C₁₋₁₀-alkyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br;-   (ii) —C(═O)-cyclopropyl, unsubstituted or mono- or disubstituted    with substituents independently of one another selected from the    group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃;-   (iii) —C(═O)-cyclobutyl, unsubstituted or mono- or disubstituted    with substituents independently of one another selected from the    group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN and —OCH₃;-   (iv) —C(═O)-2-tetrahydrofuranyl, unsubstituted;-   (v) —C(═O)-(5- to 6-membered heteroaryl), wherein said 5- to    6-membered heteroaryl is selected from the group consisting of    thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2,4-diazolyl,    1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case    said 5- to 6-membered heteroaryl is unsubstituted or mono- or    disubstituted with substituents independently of one another    selected from the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN,    ═O, and —OCH₃;-   (vi) —S(═O)₂—C₁₋₁₀-alkyl, unsubstituted;-   (vii) —S(═O)₂-cyclopropyl, unsubstituted;-   (viii) —S(═O)₂—CH₂₋cyclopropyl, unsubstituted; or-   (ix) —S(═O)₂-(5- to 6-membered heteroaryl), wherein said 5- to    6-membered heteroaryl is selected from the group consisting of    thiazolyl, pyrazolyl, oxazolyl and 1-oxa-2,4-diazolyl,    1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, wherein in each case    said 5- to 6-membered heteroaryl is unsubstituted or mono- or    disubstituted with substituents independently of one another    selected from the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN,    ═O, and —OCH₃.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), R₃ represents —C₁₋₁₀-alkyl;—C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl;—C₁₋₆-alkylene-aryl; —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-aryl;—C(═O)—C₁₋₆-alkylene-aryl; —S(═O)₁₋₂—C₁₋₁₀-alkyl;—S(═O)₁₋₂—C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂-aryl; or —S(═O)₁₋₂—C₁₋₆-alkylene-aryl.

In a preferred embodiment, R₃ represents —C₁₋₁₀-alkyl;—C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl;—C₁₋₆-alkylene-aryl.

In particularly preferred embodiments, R₃ represents

-   (i) —C₁₋₁₀-alkyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br;-   (ii) -cyclohexyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br;-   (iii) —CH₂-cyclopropyl, unsubstituted;-   (iv) —CH₂-cyclohexyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br;-   (v) phenyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃; or-   (vi) —CH₂-phenyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), R₄ represents —H; —F; —Cl; —Br; —I; —CN;—CH₃; —CF₃; —CF₂H; —CFH₂ or cyclopropyl.

In a preferred embodiment, R₄ represents —H.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), X represents N or CR₅; wherein R₅represents —H; —F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl.

In a preferred embodiment, X represents N or CH.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), Y represents N or CR₆; wherein R₆represents —H; —F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl.

In a preferred embodiment, Y represents N or CH.

In the compound of the invention according to any of general formulas(I), (II), (III), (IV) or (V), Z represents N or CR₇; wherein R₇represents —H; —F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl.

In a preferred embodiment, Z represents N or CH.

In particularly preferred embodiments,

-   (i) X represents CR₅, preferably CH; Y represents CR₆, preferably    CH; and Z represents CR₇, preferably CH; or-   (ii) X represents N; Y represents CR₆, preferably CH; and Z    represents CR₇, preferably CH; or-   (iii) X represents CR₅, preferably CH; Y represents N; and Z    represents CR₇, preferably CH; or-   (iv) X represents CR₅, preferably CH; Y represents CR_(G),    preferably CH; and Z represents N; or-   (v) X represents N; Y represents N; and Z represents CR₇, preferably    CH; or-   (vi) X represents N; Y represents CR₆, preferably CH; and Z    represents N; or-   (vii) X represents CR₅, preferably CH; Y represents N; and Z    represents N; or-   (viii) X represents N; Y represents N; and Z represents N.    In particularly preferred embodiments of the invention according to    any of general formulas (I),    R₁ represents phenyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃; and/or    R₂ represents —C(═O)—C₁₋₆-alkyl; —C(═O)-cyclopropyl; or    —C(═O)-cyclobutyl, unsubstituted or mono- or disubstituted with    substituents independently of one another selected from the group    consisting of —F, —Cl, and —Br; and/or    R₃ represents fluoro-phenyl.

In a preferred embodiment, the compound according to the invention isselected from the group consisting of

-   1    2,2-difluoro-N-[rac-(2R,3S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   2    2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   3    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   4    2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]propanamide-   5    2,2-difluoro-N-[rac-(2R,3S)-2-(2,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   6    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3,4-difluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   7    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]propanamide-   8    N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide-   9    N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanesulfonamide-   10    N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide-   11    2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   12    N-[(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propanamide-   13    1-methyl-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   14    1-fluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   15    N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide-   16    N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide-   17    N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide-   18    1-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   19    N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide-   20    2,2-difluoro-N-[(2S,3R)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   21    2,2-difluoro-N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   22    1-methyl-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   23    1-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   24    2,2-difluoro-N-[(2S,3R)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   25    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   26    2,2-difluoro-N-[rac-(2R,3S)-2-(3,5-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   27    2,2-difluoro-N-[rac-(2R,3S)-5-oxo-2-phenyl-1-(1-phenylindazol-5-yl)pyrrolidin-3-yl]propanamide-   28    N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   29    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   30    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   31    2,2-difluoro-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   32    N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide-   33    2,2-difluoro-N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   34    N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   36    2,2-difluoro-N-[rac-(2S,3S)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   37    1-cyclopropyl-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide-   38    2,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide-   39    N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide-   42    2,2-difluoro-N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   43    N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   45 1:1 mixture of (1    S,2S)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide    and (1    S,2S)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   46    rac-(1S,2R)-2-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   48    2,2-difluoro-N-[rac-(2S,3R)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   49    N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   51    N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide-   52    2-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   53    N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   54    N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   55    N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   56 1:1 mixture of    (1R,2R)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide    and    (1R,2R)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   61    N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   62    N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   63 1:1 mixture of    (1R,2R)-2-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide    and    (1R,2R)-2-fluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   65    N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide-   66    N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]acetamide-   67    N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   68    2,2-difluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   69    2,2-difluoro-N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   70    1-fluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide-   71    N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide-   72    2,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide-   73    1-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide-   74    N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-cyclopropanecarboxamide-   75    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4,4-difluorocyclohexyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   76    2,2-difluoro-N-[rac-(2R,3S)-1-(1-cyclohexylindazol-5-yl)-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   77    2,2-difluoro-N-[rac-(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-(1-methylindazol-5-yl)-5-oxo-pyrrolidin-3-yl]propanamide-   78    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(2,2-difluoroethyl)indazol-5-yl]-2-(2-fluoro-5-methoxy-phenyl)-5-oxo-pyrrolidin-3-yl]propanamide-   79    2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   80    2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   81    2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   82    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(cyclopropylmethyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   84    2,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4,4-difluorocyclohexyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide-   85    2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   86    2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   87    2,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide-   88    N-[(2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl]-2,2-difluoropropanamide-   89    2,2-difluoro-N-[rac-(2R,3S)-2-ethyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide-   90    2,2-difluoro-N-[rac-(2R,3R)-2-(cyclopropylmethyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide-   91    2-cyclopropyl-N-[(2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]acetamide-   92    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide-   93    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1H-imidazole-2-carboxamide-   94    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-2-methyloxazole-5-carboxamide-   95    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-5-methylthiazole-4-carboxamide-   96    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]pyrimidine-2-carboxamide-   97    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]nicotinamide-   98    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]oxetane-3-carboxamide-   99    N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]thiazole-5-sulfonamide-   100    N-[rac-(2R,3R)-2-(5-chlorothiophen-2-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]cyclopropanesulfonamide-   101    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide-   102    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide-   103    2,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide    in each case in the form of the free compound or a physiologically    acceptable salt thereof.

The compounds according to the invention can be synthesized by standardreactions in the field of organic chemistry known to the person skilledin the art or in a manner as described herein (cf. Reaction Schemesbelow) or analogously. The reaction conditions in the synthesis routesdescribed herein are known to the skilled person and are for some casesalso exemplified in the Examples described herein.

Substituted indazole moieties in compounds of formula (D) and formula(F) are introduced by subjecting lactam (B) or lactam (E) in aregioselective metal catalyzed C—N coupling reaction with correspondingindazole halides (C), preferred with corresponding indazole iodides.Metal catalyzed C—N coupling reactions are generally known in the art(Current Organic Synthesis, 2011, 8, 53). Favorable C—N couplingreactions are palladium and copper catalyzed cross-coupling reactions(Chem. Rev., 2016, 116, 12564; Chem. Soc. Rev., 2014, 43, 3525; Chem.Sci., 2010, 1, 13). Regioselective C—N couplings with arylhalides areknown in the art (Chem. Sci., 2011, 2, 27; J. Am. Chem. Soc., 2001, 123,7727).

Primary amines (A) and (G) are converted to corresponding amides andsulfonamides (acylation and sulfonamide formation) (B) and (D) usingcommercially available acids (activation of acids using e.g. HATU) oracid chlorides under standard amide coupling reaction conditions(March's Advanced Organic Chemistry, 2007, 6th Edition, page 1427-1474).

Introduction of different orthogonal protecting groups PG (e.g. Boc,Cbz) to convert (A) to (E) as well as deprotection of compounds offormula (E) to (A) is well described in the literature (T. W. Green, P.G. M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience,New York, 1999).

Compounds (A) and (E) can be synthesized according to procedures whichare described in the literature.

Route 1:

Compounds of formula (A) and (E) can be synthesized starting fromcompounds of formula (H) (J. Org. Chem., 2010, 76, 948).

Route 2:

Synthesis of compounds of formula (M) and (L) is described in theliterature (J. Org. Chem., 2007, 72, 5016; Org. Lett., 2007, 9, 4077; J.Org. Chem., 2012, 77, 160). Compounds of formula (A) and (E) can besynthesized using Curtius rearrangement as key step to convertcarboxylic acid (L) to corresponding primary amine (A) or (E). Curtiusrearrangement is well known in the art (Tetrahedron Letters, 2010, 385).

Route 3:

Synthesis of compounds of formula (J) is described in the literature(Org. Lett., 2009, 11, 4512; ACS Sustainable Chem. Eng., 2015, 3, 1873).Reduction of highly functionalized lactams (J) gives an alternate routefor synthesis of compounds of formula (A) and (E). Reduction of nitrogroups is well known in the art (March's Advanced Organic Chemistry,2007, 6th Edition, page 1815f).

Route 4:

Synthesis of compounds of formula (K) is described in the literature (J.Heterocyclic Chem., 2014, 51, E25). Reduction of highly functionalizedlactams (K) gives an alternate route for synthesis of compounds offormula (A) and (E). Reduction of enamides/imines is well known in theart (March's Advanced Organic Chemistry, 2007, 6th Edition, page 1053fand page 1811f).

Compounds of formula (D) can be synthesized via regioselective C—Ncoupling of compound (O). Suitable C—N coupling reactions for N—Hcontaining heterocycles are known in the art (Synthesis, 2011, 829;Chem. Sci., 2011, 2, 27; Beilstein J. Org. Chem., 2011, 7, 59; J. Org.Chem., 2004, 69, 5578). Compound of formula (0) is synthesized viadeprotection of compound (N) under acidic conditions.

The compounds according to the invention can be produced in the mannerdescribed here or in an analogous manner.

In a preferred embodiment, the compounds according to the invention aremodulators of the glucocorticoid receptor. In the sense of theinvention, the term “selective modulator of the glucocorticoid receptor(glucocorticoid receptor modulator)” preferably means that therespective compound exhibits in a cellular target engagement assay foragonistic or antagonistic potency on the glucocorticoid receptor an EC50or IC50 value on the glucocorticoid receptor of at most 15 μM (10·10⁻⁶mol/L) or at most 10 μM; more preferably at most 1 μM; still morepreferably at most 500 nM (10⁻⁹ mol/L); yet more preferably at most 300nM; even more preferably at most 100 nM; most preferably at most 10 nM;and in particular at most 1 nM. In a preferred embodiment, the compoundaccording to the invention exhibits in a cellular target engagementassay for agonistic or antagonistic potency on the glucocorticoidreceptor an EC50 or IC50 value on the glucocorticoid receptor in therange of from 1 μM to 15 μM, more preferably from 100 nM to 1 μM, mostpreferably below 100 nM.

The person skilled in the art knows how to test compounds for modulation(agonistic or antagonistic) of the activity of the glucocorticoidreceptor. Preferred target engagement assays for testing compounds fortheir agonistic or antagonistic potency (EC50, IC50) on theglucocorticoid receptor are described herein below:

Glucocorticoid Receptor Cell-Based Assays

Potential selective glucocorticoid receptor modulators of thisintervention can be tested for modulation of the activity of theglucocorticoid receptor using cell-based assays. These assays involve aChinese hamster ovary (CHO) cell line which contains fragments of theglucocorticoid receptor as well as fusion proteins. The glucocorticoidreceptor fragments used are capable of binding the ligand (e.g.beclomethasone) to identify molecules that compete for binding withglucocorticoid receptor ligands. In more detail, the glucocorticoidreceptor ligand binding domain is fused to the DNA binding domain (DBD)of the transcriptionfactor GAL4 (GAL4 DBD-GR) and is stably integratedinto a CHO cell line containing a GAL4-UAS-Luciferase reporterconstruct. To identify selective glucocorticoid receptor modulators, thereporter cell line is incubated with the molecules using an 8-pointhalf-log compound dilution curve for several hours. After cell lysis theluminescence that is produced by luciferase after addition of thesubstrate is detected and EC50 or IC50 values can be calculated.Engagement of molecules which induce gene expression via glucocortocoidreceptor binding to the DNA leads to expression of the luciferase geneunder the control of the fusion protein GAL4 DBD-GR and therefore to adose-dependent increase of the luminescence signal. Binding of moleculeswhich repress beclomethasone-induced gene expression of the luciferasegene under the control of the fusion protein GAL4 DBD-GR leads to adose-dependent reduction of the luminescence signal.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor of at most 1 μM (10⁻⁶ mol/L); stillmore preferably at most 500 nM (10⁻⁹ mol/L); yet more preferably at most300 nM; even more preferably at most 100 nM; most preferably at most 50nM; and in particular at most 10 nM or at most 1 nM.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor in the range of from 1 μM to 15 μM,more preferably from 100 nM to 1 μM, most preferably below 100 nM.

In a preferred embodiment, the compound according to the inventionexhibits in a cellular target engagement assay for agonistic orantagonistic potency on the glucocorticoid receptor an EC50 or IC50value on the glucocorticoid receptor in the range of from 0.1 nM (10⁻⁹mol/L) to 1000 nM; still more preferably 1 nM to 800 nM; yet morepreferably 1 nM to 500 nM; even more preferably 1 nM to 300 nM; mostpreferably 1 nM to 100 nM; and in particular 1 nM to 80 nM.

Preferably, the compounds according to the invention are useful asselective modulators of the glucocorticoid receptor.

Therefore, the compounds according to the invention are preferablyuseful for the in vivo treatment or prevention of diseases in whichparticipation of the glucocorticoid receptor is implicated.

The invention therefore further relates to a compound according to theinvention for use in the modulation of glucocorticoid receptor activity.

Therefore, another aspect of the invention relates to a compoundaccording to the invention for use in the treatment and/or prophylaxisof a disorder which is mediated at least in part by the glucocorticoidreceptor. Still another aspect of the invention relates to a method oftreatment of a disorder which is mediated at least in part by theglucocorticoid receptor comprising the administration of atherapeutically effective amount of a compound according to theinvention to a subject in need thereof, preferably a human.

A further aspect of the invention relates to the use of a compoundaccording to the invention as medicament.

Another aspect of the invention relates to a pharmaceutical dosage formcomprising a compound according to the invention. Preferably, thepharmaceutical dosage form comprises a compound according to theinvention and one or more pharmaceutical excipients such asphysiologically acceptable carriers, additives and/or auxiliarysubstances; and optionally one or more further pharmacologically activeingredient. Examples of suitable physiologically acceptable carriers,additives and/or auxiliary substances are fillers, solvents, diluents,colorings and/or binders. These substances are known to the personskilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe furPharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).

The pharmaceutical dosage form according to the invention is preferablyfor systemic, topical or local administration, preferably for oraladministration. Therefore, the pharmaceutical dosage form can be in formof a liquid, semisolid or solid, e.g. in the form of injectionsolutions, drops, juices, syrups, sprays, suspensions, tablets, patches,films, capsules, plasters, suppositories, ointments, creams, lotions,gels, emulsions, aerosols or in multiparticulate form, for example inthe form of pellets or granules, if appropriate pressed into tablets,decanted in capsules or suspended in a liquid, and can also beadministered as such.

The pharmaceutical dosage form according to the invention is preferablyprepared with the aid of conventional means, devices, methods andprocesses known in the art. The amount of the compound according to theinvention to be administered to the patient may vary and is e.g.dependent on the patient's weight or age and also on the type ofadministration, the indication and the severity of the disorder.Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, mostpreferably 0.05 to 50 mg of a compound according to the invention areadministered per kg of the patient's body weight.

The glucocorticoid receptor is believed to have potential to modify avariety of diseases or disorders in mammals such as humans. Theseinclude in particular inflammatory diseases, asthma, rheumatoidarthritis, inflammatory bowel disease, chronic obstructive pulmonarydisease, acute respiratory distress syndrome, cystic fibrosis,osteoarthritis, polymyalgia rheumatica, giant cell arteritis, Sjögrensyndrome, Duchenne muscular dystrophy, vasculitis, Behçet's disease,ulcerative colitis and Crohn's disease.

Further diseases and disorders that are believed to be modulated by theglucocorticoid receptor include endocrine disorders, preferably selectedfrom primary or secondary adrenocortical insufficiency, congenitaladrenal hyperplasia, hypercalcemia associated with cancer, andnonsuppurative thyroiditis; rheumatic disorders; preferably selectedfrom psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondilitis, acute and subacute bursistis, acutenonspecific tenosynovitis, acute gouty arthritis, post-traumaticosteoarthritis, synovitis of osteoarthritis and epicondylitis; collagendiseases, preferably selected from systemic lupus erythematosus,systemic dermatomyositis (polymyositis) and acute rheumatic carditis;dermatologic diseases, preferably selected from pemphigus, bullousdermatitis herpetiformis, severe erythema multiforme (Stevens-Johnsonsyndrome), exfoliative dermatitis, mycosis fungoides, psoriasis andseborrheic dermatitis; allergic states, preferably selected fromseasonal or perennial allergic rhinitis, bronchial asthma, contactdermatitis, atopic dermatitis, serum sickness and drug hypersensitivityreactions; ophthalmis diseases, preferably selected from allergiccorneal marginal ulcers, herpes zoster ophthalmicus, anterior segmentinflammation, diffuse posterior uveitis and choroiditis, sympatheticophthalmia, allergic conjunctivitis, keratitis, chorioretinitis, opticneuritis, iritis and iridocyclitis; respiratory diseases, preferablyselected from symptomatic sarcoidosis, Loeffler's syndrome, berylliosis,fulminating or disseminated pulmonary tubercolosis when usedconcurrently with antituberculous chemotherapy, aspiration pneumonitis;hematologic disorders, preferably selected from idiopathicthrombocytopenic purpura, secondary thrombocytopenia, aquired(autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia),congenital (erythroid) hypoplastic anemia; neoplastic diseases,preferably selected from leukemias and lyphomas, acute leukemia ofchildhood; gastrointestinal diseases, preferably selected fromulcerative colitis and regional enteritis.

Another aspect of the invention relates to a compound according to theinvention for use in the treatment and/or prophylaxis of pain and/orinflammation; more preferably inflammatory pain.

Another aspect of the invention relates to a compound according to theinvention for use in the treatment and/or prophylaxis of asthma,rheumatoid arthritis, inflammatory bowel disease, chronic obstructivepulmonary disease, acute respiratory distress syndrome, cystic fibrosis,osteoarthritis, polymyalgia rheumatica, giant cell arteritis, Sjögrensyndrome, Duchenne muscular dystrophy, vasculitis, Behçet's disease,ulcerative colitis and/or Crohn's disease.

Still another aspect of the invention relates to a compound according tothe invention for use in the treatment and/or prophylaxis of endocrinedisorders, preferably selected from primary or secondary adrenocorticalinsufficiency, congenital adrenal hyperplasia, hypercalcemia associatedwith cancer, and nonsuppurative thyroiditis; rheumatic disorders;preferably selected from psoriatic arthritis, rheumatoid arthritis,juvenile rheumatoid arthritis, ankylosing spondilitis, acute andsubacute bursistis, acute nonspecific tenosynovitis, acute goutyarthritis, post-traumatic osteoarthritis, synovitis of osteoarthritisand epicondylitis; collagen diseases, preferably selected from systemiclupus erythematosus, systemic dermatomyositis (polymyositis) and acuterheumatic carditis; dermatologic diseases, preferably selected frompemphigus, bullous dermatitis herpetiformis, severe erythema multiforme(Stevens-Johnson syndrome), exfoliative dermatitis, mycosis fungoides,psoriasis and seborrheic dermatitis; allergic states, preferablyselected from seasonal or perennial allergic rhinitis, bronchial asthma,contact dermatitis, atopic dermatitis, serum sickness and drughypersensitivity reactions; ophthalmis diseases, preferably selectedfrom allergic corneal marginal ulcers, herpes zoster ophthalmicus,anterior segment inflammation, diffuse posterior uveitis andchoroiditis, sympathetic ophthalmia, allergic conjunctivitis, keratitis,chorioretinitis, optic neuritis, iritis and iridocyclitis; respiratorydiseases, preferably selected from symptomatic sarcoidosis, Loeffler'ssyndrome, berylliosis, fulminating or disseminated pulmonarytubercolosis when used concurrently with antituberculous chemotherapy,aspiration pneumonitis; hematologic disorders, preferably selected fromidiopathic thrombocytopenic purpura, secondary thrombocytopenia, aquired(autoimmune) hemolytic anemia, erythroblastopenia (RBC anemia),congenital (erythroid) hypoplastic anemia; neoplastic diseases,preferably selected from leukemias and lyphomas, acute leukemia ofchildhood; gastrointestinal diseases, preferably selected fromulcerative colitis and regional enteritis.

A further aspect of the invention relates to a method of treatment ofpain and/or inflammation; more preferably inflammatory pain. Still afurther aspect of the invention relates to a method of treatment ofasthma, rheumatoid arthritis, inflammatory bowel disease, chronicobstructive pulmonary disease, acute respiratory distress syndrome,cystic fibrosis, osteoarthritis, polymyalgia rheumatica, giant cellarteritis, Sjögren syndrome, Duchenne muscular dystrophy, vasculitis,Behçet's disease, ulcerative colitis and/or Crohn's disease.

The following examples further illustrate the invention but are not tobe construed as limiting its scope.

The following abbreviations are used in the descriptions of theexperiments: AcOH=acetic acid; Attaphos=bis(di-tert-butyl(4dimethylaminophenyl)phosphine)dichloropalladium(II); Cbz=carboxybenzyl;DCM=dichloromethane; DEA=diethylamine; DIPEA=N,N-diisopropylethylamine;DMAP=4-(dimethylamino)-pyridine; DMF=N,N-dimethylformamid;DMSO=dimethylsulfoxid; DPPA=diphenyl phosphoryl azide; dppf=1,1′;bis(diphenylphosphanyl)ferrocene; EA=ethyl acetate; EtOAc=ethyl acetate;EtOH=ethanol;HATU=1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; h=hour; LDA=lithiumdiisopropylamide;LiHMDS=lithium bis(trimethylsilyl)amide; MeOH=methanol; min=minute;n-BuLi=n-butyllithium; sat.=saturated; RT=room temperature; Rt=retentiontime; tert=tertiary, TEA=triethylamine; TFA=trifluoro acetic acid;THF=tetrahydrofuran; p-TSA=para-toluene sulfonic acid;TMSCl=trimethylsilyl chloride.

Synthesis of trans-4-amino-5-(3-chlorophenyl)pyrrolidin-2-one(Intermediate A1)

Step 1:

Maleic anhydride (9.8 g, 100 mmol, 1.0 eq), p-thiocresol (12.4 g, 100mmol, 1.0 eq), ammonium acetate (7.8 g, 100 mmol, 1.0 eq),3-chlorobenzaldehyde (11.5 mL, 100 mmol, 1.0 eq) and toluene (100 mL)were put in a sealed tube. The reaction mixture was stirred at RT for 1h and then stirred at 150° C. for 16 h. After cooling to RT, the solventwas evaporated under reduced pressure, and the residue was basified withsat. NaHCO₃ solution and was extracted with DCM. The aqueous layer wasacidified with 2N HCl under ice cooling and the crude product wasextracted twice with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to get the crude2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylic acid(10.0 g).

Step 2:

To a stirred solution of crude2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylic acid(10.0 g, 27.7 mmol, 1.0 eq) in acetone (100 mL), potassium carbonate(15.3 g, 110.8 mmol, 4.0 eq) and methyl iodide (7.0 mL, 110.8 mmol, 4.0eq) were added at 0° C. and the reaction mixture was stirred for 16 h atRT. The solvent was removed under reduced pressure, and the residue waspartitioned between DCM and water. The aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) to givemethyl 2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (4.0 g, 38%).

Step 3:

To a stirred solution of methyl2-(3-chlorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate (10.0g, 26.66 mmol, 1.0 eq) in EtOH:THF (100 mL, 2:1), Raney Nickel (2.5 g)was added and the reaction mixture was stirred for 2 h at RT Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was then washed 2-3 times with EtOAc. The combinedorganic layers were concentrated and the crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) to givemethyl 2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate as an off whitesolid (6.0 g, 89%) (syn:anti, 1:1 mixture).

Step 4:

To a stirred solution of methyl2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylate (3.0 g, 11.85 mmol,1.0 eq) in MeOH (50 mL) was added 2 N NaOH solution (10 mL) and thereaction mixture was stirred at 80° C. for 2 h. After completion of thereaction (monitored by LCMS), the reaction mixture was concentrated andacidified with 2N HCl solution and the crude product was then extractedwith 30% isopropanol-DCM. The combined organic layers were dried overNa₂SO₄ and concentrated under reduced pressure to gettrans-2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (2.5 g,88%).

Step 5:

To a stirred solution oftrans-2-(3-chlorophenyl)-5-oxopyrrolidine-3-carboxylic acid (2.0 g, 8.36mmol, 1.0 eq) in benzene:THF (100 mL, 4:1) were added TEA (2.35 mL,16.73 mmol, 2.0 eq) and DPPA (2.35 ml, 10.8 mmol, 1.3 eq) and thereaction mixture was stirred at RT for 2 h. Then 2,4-dimethoxy benzylalcohol (1.8 g, 10.87 mmol, 1.3 eq) was added to the reaction mixtureand the reaction mixture was heated to reflux for 16 h. Aftercompletion, the reaction mixture was concentrated under reduced pressureto get the crude which was extracted with water and EtOAc. The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure to get the crude product which was purified by columnchromatography (100-200 mesh silica gel; 2% MeOH-DCM; R_(f)-value-0.5)to afford trans-2,4-dimethoxybenzyl(2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.5 g, 44%).

Step 6:

To a stirred solution of trans-2,4-dimethoxybenzyl(2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)carbamate (0.5 g, 1.23 mmol,1.0 eq) in DCM (10 mL) was added TFA (2 mL) at 0° C., and the reactionwas stirred for 3 h at RT After completion, the reaction mixture wasdiluted with EtOAc and washed with sat.NaHCO₃ solution. The combinedorganic layers were dried over Na₂SO₄ and concentrated to get thedesired trans-4-amino-5-(3-chlorophenyl)pyrrolidin-2-one as a whitesolid (0.25 g, 96%).

Synthesis of trans-4-amino-5-phenylpyrrolidin-2-one (Intermediate A2)

Step 1:

Maleic anhydride (9.8 g, 100 mmol, 1.0 eq), p-thiocresol (12.4 g, 100mmol, 1.0 eq), ammonium acetate (7.8 g, 100 mmol, 1.0 eq) andbenzaldehyde (10 mL, 100 mmol, 1.0 eq) were put in a sealed tube and 100ml toluene was added. The reaction mixture was stirred at RT for 1 h andthen stirred at 150° C. for 16 h. After cooling to RT, the solvent wasevaporated under reduced pressure, and the residue was basified withsat.NaHCO₃ solution and was extracted with DCM. The aqueous layer wasacidified with 2N HCl under ice cooling and the crude product wasextracted twice with EtOAc. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to get the crude5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0 g,crude).

Step 2:

To a stirred solution of crude5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylic acid (10.0 g,30.58 mmol, 1.0 eq) in acetone (100 mL), potassium carbonate (16.8 g,122.32 mmol, 4.0 eq) and methyl iodide (7.6 ml, 122.32 mmol, 4.0 eq)were added at 0° C., and the reaction was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, and the residue waspartitioned between DCM and water. The aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered, and concentrated. The crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) to givemethyl 5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g,38%) as an off-white solid.

Step 3:

To a stirred solution of methyl5-oxo-2-phenyl-3-(p-tolylthio)pyrrolidine-3-carboxylate (4.0 g, 11.73mmol, 1.0 eq) in EtOH:THF (100 mL, 2:1), Raney Nickel (1 g) was addedand the reaction mixture was stirred for 2 h at RT After completion, thereaction mixture was filtered through a celite bed and the celite bedwas washed 2-3 times with EtOAc. The combined organic layers wereconcentrated and the crude was purified by column chromatography(100-200 silica gel, 50% EtOAc:hexanes) to afford methyl5-oxo-2-phenylpyrrolidine-3-carboxylate (2.2 g, 88%, syn: anti, 1:1mixture) as an off-white solid.

Step 4:

To a stirred solution of methyl 5-oxo-2-phenylpyrrolidine-3-carboxylate(1.0 g, 4.56 mmol, 1.0 eq) in MeOH (25 mL) was added 2 N NaOH solution(5 mL) and the reaction mixture was stirred at 80° C. for 2 h. Aftercompletion of the reaction (monitored by LCMS), the reaction mixture wasconcentrated and acidified with 2N HCl solution and was extracted with30% isopropanol-DCM. The combined organic layers were dried over Na₂SO₄and were concentrated under reduced pressure to get the desiredtrans-5-oxo-2-phenylpyrrolidine-3-carboxylic acid (0.8 g, 85%).

Step 5:

To a stirred solution of trans-5-oxo-2-phenylpyrrolidine-3-carboxylicacid (0.5 g, 2.43 mmol, 1.0 eq) in benzene:THF (25 mL, 4:1) was addedTEA (0.68 ml, 4.87 mmol, 2.0 eq) and DPPA (0.68 ml, 3.17 mmol, 1.3 eq)and the reaction mixture was stirred at RT for 2 h. Then benzyl alcohol(0.33 mL, 3.17 mmol, 1.3 eq) was added and the reaction mixture washeated to reflux for 16 h. After completion, the reaction mixture wasconcentrated under reduced pressure to get the crude compound which wasextracted with water and EtOAc. The combined organic layers were driedover Na₂SO₄ and concentrated under reduced pressure to get the crudeproduct which was purified by column chromatography (100-200 mesh silicagel; 2% MeOH-DCM; R_(f)-value-0.5) to afford trans-benzyl(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (0.38 g, 50%).

Step 6:

To a stirred solution of trans-benzyl(5-oxo-2-phenylpyrrolidin-3-yl)carbamate (1.7 g, 5.48 mmol, 1.0 eq) inMeOH (20 mL, 2:1), Pd/C (0.058 g, 0.548 mmol, 0.1 eq) was added, and thereaction was stirred with a hydrogen balloon for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with EtOAc. The combined organiclayers were concentrated to get the desiredtrans-4-amino-5-phenylpyrrolidin-2-one as brown gum (0.9 g, 93%).

Synthesis of (4S,5R)-4-amino-5-phenylpyrrolidin-2-one (IntermediateA2-ent2)

To a stirred solution of trans-4-amino-5-phenyl-pyrrolidin-2-one(intermediate A2) (10.0 g, 0.056 mol) in EtOH (180 mL) and acetonitrile(200 mL) was added L-tartaric acid (8.5 g, 0.056 mol) at RT. Theresulting suspension was stirred at 90° C. for 1 h. To this refluxingsuspension was slowly added water (110 mL). The resulting reactionmixture was maintained at 90° C. and was stirred for 4 h. The resultingclear solution was slowly cooled to RT and was allowed to stand at RTfor 24 h. The solid thus precipitated was collected by filtration andwashed with EtOH (100 mL) to afford 7.5 g of chiral (ent-2) as thecorresponding L-tartrate salt. This solid material was treated with 1Naq. NaOH solution at RT. The resulting basic aqueous solution was thenextracted with 10% MeOH in DCM (100 mL x 5-6 times) to afford(4S,5R)-4-amino-5-phenyl-pyrrolidin-2-one (3 g, 60%) as a white solid(intermediate A2-ent2).

Enantiomeric excess (ee) determined by chiral HPLC (Column Name:Chiralpak IA (4.6×250 mm), 5 μm; Mobile Phase: Hexane/EtOH/IP amine:80/20/0.1; Flow Rate: 1.0 ml/min; RT=25.0 min): ee=99.7%

Specific Rotation: [+29.9° ] at 25° C., C=1% in EtOH.

Synthesis of (4R,5S)-4-amino-5-phenylpyrrolidin-2-one (IntermediateA2-ent1)

To a stirred solution of trans-4-amino-5-phenyl-pyrrolidin-2-one(intermediate A2) (7.0 g, 39.77 mmol) in EtOH (126 mL) and acetonitrile(140 mL) was added D-tartaric acid (5.96 g, 39.77 mmol) at RT. Theresulting suspension was stirred at 90° C. for 1 h. To this refluxingsuspension was slowly added water (77 mL). The resulting reactionmixture was maintained at 90° C. for 4 h. The resulting clear solutionwas slowly cooled to RT and was allowed to stand at RT for 24 h. Thesolid thus precipitated was collected by filtration and washed with EtOH(70 mL) to afford 5.2 g of chiral (ent-1) as the correspondingD-tartrate salt as an off-white solid.(4R,5S)-4-amino-5-phenylpyrrolidin-2-one (2R,3R)-2,3-dihydroxysuccinate(5.2 g) was treated with 1N NaOH solution at RT. The resulting basicaqueous solution was then extracted with 10% MeOH in DCM (4×50 mL) toafford (4R,5S)-4-amino-5-phenylpyrrolidin-2-one (2.4 g, 34%) as a whitesolid.

Enantiomeric excess (ee) determined by chiral HPLC (Column Name:Chiralpak IA (4.6×250 mm), 5 μm; Mobile Phase: Hexane/EtOH/IP amine:80/20/0.1; Flow Rate: 1.0 ml/min; RT=17.65 min): ee=99.1%

Specific Rotation: [−34.5° ] at 25° C., C=1.0% in EtOH.

Synthesis of trans-4-amino-5-(2,4-difluorophenyl)pyrrolidin-2-one(Intermediate A3)

Step 1:

Maleic anhydride (28.9 g, 295.7 mmol, 1.0 eq), p-thiocresol (36.6 g,295.7 mmol, 1.0 eq), ammonium acetate (22.7 g, 295.7 mmol, 1.0 eq), and2,4-difluorobenzaldehyde (42.0 g, 295.7 mmol, 1.0 eq) were put in asealed tube and 100 mL toluene was added. The reaction mixture wasstirred at RT for 1 h and was then stirred at 150° C. for 16 h. Aftercooling to RT, the solvent was evaporated under reduced pressure, andthe residue was basified with sat. NaHCO₃ solution and was extractedwith DCM. The aqueous layer was acidified with 2N HCl under ice coolingand was then extracted twice with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated toget the crude3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylic acid(120.0 g).

Step 2:

To a stirred solution of crude3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylic acid(107.0 g, crude) in acetone (600 mL), potassium carbonate (162.7 g, 1170mmol, 4.0 eq) and methyl iodide (73.3 mL, 1170 mmol, 4.0 eq) were addedat 0° C., and the reaction mixture was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, and the residue waspartitioned between DCM and water. The aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) which gavemethyl3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylate asan off white solid (6.0 g, 5%).

Step 3:

To a stirred solution of methyl3-((2,4-difluorophenyl)thio)-5-oxo-2-phenylpyrrolidine-3-carboxylate(6.0 g, 15.9 mmol, 1.0 eq) in EtOH:THF (225 mL, 2:1), Raney Nickel (60.0g) was added and the reaction was stirred for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with EtOAc. The combined organiclayers were concentrated and the crude product was purified by columnchromatography (100-200 silica gel, 50% EtOAc:hexanes) which gave methyl2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylate (2.8 g, 69%,syn:anti 1:1) as an off white solid.

Step 4:

To a stirred solution of methyl2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylate (2.0 g, 7.84 mmol,1.0 eq) in MeOH (47 mL) was added 2 N NaOH solution (12 mL) and thereaction mixture was stirred at 70° C. for 3 h. After completion of thereaction (monitored by LCMS), the reaction mixture was concentrated andacidified with 2N HCl solution and was then extracted with 30%isopropanol-DCM. The combined organic layers were dried over Na₂SO₄ andwere concentrated under reduced pressure to get the desiredtrans-2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (1.8 g,95%).

Step 5:

To a stirred solution oftrans-2-(2,4-difluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (1.8 g,7.46 mmol, 1.0 eq) in benzene:THF (60 mL, 4:1) was added TEA (2.07 mL,14.93 mmol, 2.0 eq) and DPPA (2.1 mL, 9.7 mmol, 1.3 eq) and the reactionmixture was stirred at ambient temperature for 2 h. Then benzyl alcohol(1.0 ml, 9.7 mmol, 1.3 eq) was added and the reaction mixture was heatedto reflux for 16 h. After completion, the reaction mixture wasconcentrated under reduced pressure to get the crude which was extractedwith water and EtOAc. The combined organic layers were dried over Na₂SO₄and were concentrated under reduced pressure to get the crude productwhich was purified by flash column chromatography (100-200 mesh silicagel; 2% MeOH-DCM; R_(f)-value-0.5) to afford trans-benzyl(2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.2 g, 46%) asan off-white solid.

Step 6:

To a stirred solution of trans-benzyl(2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (1.2 g, 3.46mmol, 1.0 eq) in MeOH (15 mL), Pd/C (0.12 g, 10% w/w) was added, and thereaction was stirred with a hydrogen balloon for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with EtOAc. The combined organiclayers were concentrated to get the desiredtrans-4-amino-5-(2,4-difluorophenyl)pyrrolidin-2-one (0.85 g) as anoff-white solid.

Synthesis oftrans-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidin-2-one(Intermediate A4)

Step 1:

Maleic anhydride (5.97 g, 60.9 mmol, 1.0 eq), p-thiocresol (7.55 g, 60.9mmol, 1.0 eq), ammonium acetate (4.68 g, 60.9 mmol, 1.0 eq), and2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (10.0 g, 60.9 mmol, 1.0 eq)were put in a sealed tube, followed by the addition of 80 mL of toluene.The reaction mixture was stirred at RT for 1 h and was then heated to150° C. for 16 h. After cooling to RT, the solvent was evaporated underreduced pressure, and the residue was basified with sat. NaHCO₃ solutionand was extracted with DCM. The aqueous layer was acidified with 2N HClunder ice cooling and was extracted twice with EtOAc. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated to get the crude2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (2.20 g).

Step 2:

To a stirred solution of crude2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (2.2 g, 5.707 mmol, 1.0 eq) in acetone (100 mL), potassiumcarbonate (3.2 g, 22.831 mmol, 4.0 eq) and methyl iodide (1.42 mL,22.831 mmol, 4.0 eq) were added at 0° C., and the reaction was stirredfor 16 h at RT. The solvent was removed under reduced pressure, and theresidue was partitioned between DCM and water. The aqueous layer wasextracted twice with DCM. The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by column chromatography (100-200 silica gel, 50%EtOAc:hexanes) which gave methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (0.9 g, 41%).

Step 3:

To a stirred solution of methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(0.9 g, 2.253 mmol, 1.0 eq) in EtOH:THF (60 mL, 2:1), Raney Nickel (1.0g) was added, and the reaction was stirred for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with EtOAc. The combined organiclayers were concentrated and the crude remains were purified by columnchromatography (100-200 silica gel, 50% EtOAc:hexanes) which gave methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylate(0.6 g, 96%, syn:anti, 1:1) as an off white solid.

Step 4:

To a stirred solution of methyl2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylate(0.7 g, 2.524 mmol, 1.0 eq) in MeOH (15 mL) was added a 2 N NaOHsolution (3.7 mL) and the reaction mixture was stirred at 80° C. for 2h. After completion of the reaction (monitored by LCMS), the reactionmixture was concentrated and acidified with 2N HCl solution and was thenextracted with 30% isopropanol-DCM. The organic layer was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to get thedesiredtrans-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylicacid (0.5 g, 75%).

Step 5:

To a stirred solution oftrans-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylicacid (0.3 g, 1.139 mmol, 1.0 eq) in benzene:THF (15 mL, 4:1) were addedTEA (0.31 mL, 4.87 mmol, 2.0 eq) and DPPA (0.32 mL, 1.48 mmol, 1.3 eq)and the reaction mixture was stirred at RT for 2 h. Then benzyl alcohol(3 mL) was added and the reaction mixture was heated to reflux for 16 h.After completion, the reaction mixture was concentrated under reducedpressure to give the crude which was extracted with water and EtOAc. Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to get the crude product which was purified by columnchromatography (100-200 mesh silica gel; 2% MeOH-DCM; R_(f)-value-0.5)to afford trans-benzyl(−2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(0.2 g, 47%).

Step 6:

To a stirred solution of trans-benzyl(−2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(0.32 g, 0.869 mmol, 1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (50.0 mg)was added and the reaction was stirred with a hydrogen balloon for 2 hat RT. After completion, the reaction mixture was filtered through acelite bed and the celite bed was washed 2-3 times with EtOAc. Thecombined organic layer was concentrated to get the desiredtrans-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidin-2-one(0.2 g, 98%) as brown gum.

Synthesis of trans-4-amino-5-(3-fluorophenyl)pyrrolidin-2-one(Intermediate A5)

Step 1:

Maleic anhydride (19.7 g, 201.61 mmol, 1.0 eq), p-thiocresol (25.0 g,201.61 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (33.6 g, 201.61 mmol,1.0 eq), and 3-fluorobenzaldehyde (25.0 g, 201.61 mmol, 1.0 eq) were putin a round-bottom flask followed by the addition of 250 mL toluene. Thereaction mixture was refluxed for 16 h with vigorous stirring. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wascooled to RT and the solvent was evaporated under reduced pressure toafford crude1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (89.0 g, 89%) as a gummy liquid which was used in the next stepwithout further purification.

Step 2:

To a stirred solution of1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (99.7 g, 201.4 mmol, 1.0 eq) in acetone (1 L), potassium carbonate(111.3 g, 805.6 mmol, 4.0 eq) and methyl iodide (51.0 mL, 805.6 mmol,4.0 eq) were added at 0° C. and the reaction was stirred for 16 h at RT.After completion of the reaction (monitored by TLC), the solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc and water. The aqueous layer was extracted twice with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by columnchromatography (100-200 silica gel, 40% EtOAc in hexane) to affordmethyl1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(79.0 g, 77%) as an off white solid.

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(78.0 g, 153.2 mmol, 1.0 eq) in acetonitrile (500 mL), was added CAN(251.9 g, 459.6 mmol, 3.0 eq) dissolved in water dropwise at 0° C.through an addition funnel. The reaction mixture was then stirred at RTfor 16 h. After completion of the reaction (monitored by TLC), thereaction mixture was diluted with water and extracted twice with EtOAc.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography (230-400 silica gel, 40-50% EtOAc: hexane) to affordmethyl 2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(47.0 g, 85%) as an off white solid.

Step 4:

To a stirred solution of methyl2-(3-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate (30.0g, 83.5 mmol, 1.0 eq) in EtOH:THF (500 mL:500 mL, 1:1), Raney Nickel(20.0 g) was added and the reaction was stirred under a hydrogenatmosphere for 16 h at RT. After completion (monitored by TLC) thereaction mixture was filtered through a celite bed and the celite bedwas and washed 4-5 times with THF. The filtrate was concentrated toafford methyl 2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (15.2 g,77%, syn:anti mixture) as a white solid.

Step 5:

To a stirred solution of methyl2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (16.0 g, 67.4 mmol,1.0 eq) in MeOH (320 mL) was added 2 N NaOH solution (75 mL) and thereaction mixture was stirred at 80° C. for 16 h. After completion of thereaction (monitored by TLC) the reaction mixture was concentrated andacidified with 2N HCl solution to get a solid which was filtered off andwas washed with diethyl ether, and was then dried under vacuum to affordtrans-2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (9.3 g,62%).

Step 6:

To a stirred solution oftrans-2-(3-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (13.0 g,58.3 mmol, 1.0 eq) in toluene (130 mL) was added TEA (8.5 mL, 61.2 mmol,1.05 eq) and DPPA (19.3 g, 70.0 mmol, 1.2 eq) and the reaction mixturewas stirred at 90° C. for 30 min. Then benzyl alcohol (12.6 g, 116.6mmol, 2.0 eq) was added and the reaction mixture was heated to refluxfor 16 h. After completion (monitored by TLC), the reaction mixture wasconcentrated under reduced pressure. The residue was then diluted withEtOAc (100 mL), washed with water (2×100 mL), dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to get the crude productwhich was purified by column chromatography (230-400 mesh silica gel;0-2% MeOH in DCM) to afford trans-benzyl(2-(3-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (7.0 g, 37%).

Step 7:

To a stirred solution of trans-benzyl(2-(3-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (7.0 g, 21.3 mmol,1.0 eq) in MeOH (50 mL) and THF (20 mL), Pd—C (1.5 g, 14.9 mmol, 0.7 eq)was added and the reaction mixture was stirred with a hydrogen balloonfor 2 h at RT. After completion (monitored by TLC), the reaction mixturewas filtered through a celite bed and the celite bed was washed 2-3times with THF. The filtrate was concentrated to get the desiredtrans-4-amino-5-(3-fluorophenyl)pyrrolidin-2-one (3.8 g, 92%) as a browngum.

Synthesis of trans-4-amino-5-(2-fluorophenyl)pyrrolidin-2-one(Intermediate A6)

Step 1:

Maleic anhydride (19.7 g, 201.4 mmol, 1.0 eq), p-thiocresol (25.0 g,201.4 mmol, 1.0 eq), 2,4 dimethoxy benzylamine (33.6 g, 201.4 mmol, 1.0eq), and 2-fluorobenzaldehyde (25.0 g, 201.4 mmol, 1.0 eq) were taken upin 300 mL of toluene. The reaction mixture was refluxed for 16 h withvigorous stirring. After completion of the reaction (monitored by TLC,TLC system 5% MeOH in DCM, R_(f)-0.1), the reaction mixture was cooledto RT and the solvent was evaporated under reduced pressure to affordthe crude1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid as a gummy liquid (95.0 g, 95%) which was used in the next stepwithout further purification.

Step 2:

To a stirred solution of crude1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (95.0 g, 191.7 mmol, 1.0 eq) in acetone (1 L), potassium carbonate(111.3 g, 805.0 mmol, 4.2 eq) and methyl iodide (50.0 mL, 805.0 mmol,4.2 eq) were added at 0° C., and the reaction mixture was stirred at RTfor 16 h. After completion of the reaction (monitored by TLC; TLC system30% EtOAc in hexane, R_(f)-0.3), the solvent was removed under reducedpressure and the residue was partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(100-200 silica gel, 40% EtOAc in hexane) to afford the desired methyl1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (55.0 g, 56%).

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(55.0 g, 108.0 mmol, 1.0 eq) in acetonitrile (300 mL), CAN (178.0 g,324.0 mmol, 3.0 eq) in water (300 mL) was added dropwise at 0° C.through an addition funnel. The reaction mixture was then stirred at RTfor 16 h. After completion of the reaction (monitored by TLC, TLC system50% EtOAc in hexane, Rf-0.3), the reaction mixture was diluted withwater and extracted twice with EtOAc. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude product was purified by column chromatography (230-400 silica gel,40-50% EtOAc: hexane) which gave methyl2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate as anoff white solid (15.0 g, 39%).

Step 4:

To a stirred solution of methyl2-(2-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate (15.0g, 41.7 mmol, 1.0 eq) in EtOH:THF (300:300 mL, 1:1), Raney Nickel (15 g)was added, and the reaction was stirred under a hydrogen atmosphere for16 h at RT. After completion, (monitored by TLC, TLC system 70% EtOAc inhexane, Rf-0.4) the reaction mixture was filtered through a celite bedand the celite bed was washed 4-5 times with THF. The filtrate wasconcentrated to afford methyl2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylate as a white solid (9.0g, 91%; syn:anti mixture).

Step 5:

To a stirred solution of methyl2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g, 37.9 mmol, 1.0eq) in MeOH (180 mL) was added 2 N NaOH solution (40 mL) and thereaction mixture was stirred at 80° C. for 16 h. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.1), thereaction mixture was concentrated and acidified with 2N HCl solution toget a solid which was filtered off and was then washed with diethylether and dried under vacuum to affordtrans-2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (7.0 g,83%).

Step 6:

To a stirred solution oftrans-2-(2-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (7.0 g, 31.4mmol, 1.00 eq) in Toluene (80 mL) was added TEA (4.6 mL, 33.0 mmol, 1.05eq) and DPPA (10.4 g, 37.7 mmol, 1.2 eq) and the reaction mixture wasstirred at 90° C. for 30 min. Then benzyl alcohol (6.8 g, 62.8 mmol, 2.0eq) was added and the reaction mixture was heated to reflux for 16 h.After completion (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3),the reaction mixture was concentrated under reduced pressure and wasthen diluted with EtOAc (100 mL), washed with water (2×100 mL), driedover Na₂SO₄ and concentrated under reduced pressure to get the crudeproduct which was purified by column chromatography (230-400 mesh silicagel; 0-2% MeOH in DCM) to afford trans-benzyl(2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.7 g, 46%).

Step 7:

To a stirred solution of trans-benzyl(2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.7 g, 14.3 mmol,1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (2.0 g, 10% moist) was added, andthe reaction was stirred with a hydrogen balloon for 2 h at RT. Aftercompletion, (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.2), thereaction mixture was filtered through a celite bed and the celite bedwas washed 2-3 times with THF. The filtrate was concentrated to get thedesired trans-4-amino-5-(2-fluorophenyl)pyrrolidin-2-one as a brown gum(2.5 g, 90%).

Synthesis of trans-4-amino-5-(4-fluoro-3-methoxyphenyl)pyrrolidin-2-one(Intermediate A7)

Step 1:

Maleic anhydride (14.6 g, 149.7 mmol, 1.0 eq), p-thiocresol (18.5 g,149.7 mmol, 1.0 eq), 2,4-di-methoxy benzyl amine (25.0 g, 149.7 mmol,1.0 eq), and 4-fluoro-3-methoxy benzaldehyde (23.0 g, 149.7 mmol, 1.0eq) were dissolved in 500 mL toluene in a two neck round bottom flaskfitted with a dean stark trap and a condenser. The reaction mixture wasthen heated to 150° C. for 16 h. After cooling to RT, the solvent wasevaporated under reduced pressure to get the crude1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)-pyrrolidine-3-carboxylicacid which was taken to the next step without further purification.

Step 2:

To a stirred solution of crude1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (max. 149.7 mmol, 1.0 eq) in acetone (500 mL), potassium carbonate(82.0 g, 598.0 mmol, 4.0 eq) and methyl iodide (37.5 mL, 598.0 mmol, 4.0eq) were added at 0° C., and the reaction was stirred for 16 h at RT.The solvent was removed under reduced pressure, and the residue waspartitioned between DCM and water. The aqueous layer was extracted twicewith DCM. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (100-200 silica gel, 50% EtOAc:hexanes) which gavemethyl1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(72.0 g, 88%) as an off white solid.

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(70.0 g, 129.0 mmol, 1.0 eq) in acetonitrile: water (500 mL 1:1), CANwas added at 0° C. and the reaction was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, and the residue waspartitioned between EtOAc and water. The aqueous layer was extractedtwice with EtOAc. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude product waspurified by column chromatography (100-200 silica gel, 50%EtOAc:hexanes) which gave methyl2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(25.0 g, 50%) as an off white solid.

Step 4:

To a stirred solution of methyl2-(4-fluoro-3-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(15.0 g, 64.3 mmol, 1.0 eq) in EtOH:THF (300 mL, 2:1), Raney Nickel (5.0g) was added, and the reaction was stirred for 2 h at RT. Aftercompletion, the reaction mixture was filtered through a celite bed andwashed 2-3 times with EtOAc. The combined organic layers wereconcentrated and the crude product was purified by column chromatography(100-200 silica gel, 50% EtOAc:hexanes) which gave methyl2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (10.0 g,98%, syn:anti, 1:1 mixture) as an off white solid.

Step 5:

To a stirred solution of methyl2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (10.0 g,37.5 mmol, 1.0 eq) in MeOH (250 mL) was added 2 N NaOH solution (50 mL)and the reaction mixture was stirred at 80° C. for 2 h. After completionof the reaction (monitored by LCMS), the reaction mixture wasconcentrated, acidified with 2N HCl solution and then extracted with 30%isopropanol-DCM. The combined organic layers were dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to get the desiredtrans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid(8.0 g, 84%).

Step 6:

To a stirred solution oftrans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid(2.0 g, 7.90 mmol, 1.0 eq) in benzene:THF (100 mL, 4:1) was added TEA(2.2 mL, 15.81 mmol, 2.0 eq) and DPPA (2.2 mL, 10.27 mmol, 1.3 eq) andthe reaction mixture was stirred at RT for 2 h. Then benzyl alcohol (1.0mL, 10.27 mmol, 1.3 eq) was added to the reaction mixture and heated toreflux for 16 h. After completion, reaction mixture was concentratedunder reduced pressure to get the crude which was extracted with waterand EtOAc. Organic layer was dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to get the crude product which waspurified by column chromatography (100-200 mesh silica gel; 2% MeOH-DCM;Re-value-0.5) to afford trans-benzyl(2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (1.4 g,50%).

Step 7:

To a stirred solution of trans-benzyl(2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (7 g, 19.55mmol, 1 eq) in MeOH:THF (20 mL, 2:1), Pd—C (0.7 g) was added, and thereaction was stirred for 2 h at RT. After completion, the reactionmixture was filtered through celite bed and washed 2-3 times with EtOAc.The combined organic layer was concentrated to gettrans-4-amino-5-(4-fluoro-3-methoxyphenyl)pyrrolidin-2-one (4 g, 91%) asbrown gum.

Synthesis of trans-4-amino-5-(4-fluorophenyl)pyrrolidin-2-one(Intermediate A8)

Step 1:

Maleic anhydride (19.7 g, 201.6 mmol, 1.0 eq), p-thiocresol (25.0 g,201.6 mmol, 1.0 eq), 2,4 dimethoxy benzylamine (33.6 g, 201.6 mmol, 1.0eq), and 4-fluorobenzaldehyde (25.0 g, 201.6 mmol, 1.0 eq) were taken upin 250 mL toluene. The reaction mixture was refluxed for 16 h withvigorous stirring. After completion of the reaction (monitored by TLC,TLC system 5% MeOH in DCM, R₁-0.1), the reaction mixture was cooled toRT and the solvent was evaporated under reduced pressure to give crude1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (92.0 g, 92%) as a gummy liquid, which was used in the next stepwithout further purification.

Step 2:

To a stirred solution of crude1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (92.0 g, 201.4 mmol, 1.0 eq) in acetone (1 L), potassium carbonate(111.3 g, 805.6 mmol, 4.0 eq) and methyl iodide (50.0 mL, 805.6 mmol,4.0 eq) were added at 0° C. and the reaction was stirred for 16 h at RT.After completion of the reaction (monitored by TLC), the solvent wasremoved under reduced pressure and the residue was partitioned betweenEtOAc and water. The aqueous layer was extracted twice with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by columnchromatography (100-200 silica gel, 40% EtOAc in hexane) to affordmethyl1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(79.0 g, 84%) as an off white solid.

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(92.0 g, 180.7 mmol, 1.0 eq) in acetonitrile, CAN (297.0 g, 542.1 mmol,3.0 eq) in water was added dropwise to the reaction mixture at 0° C.through an addition funnel. The reaction was then stirred at RT for 16h. After completion of the reaction (monitored by TLC, TLC system 50%EtOAc in hexane, Rf-0.3), the reaction mixture was diluted with waterand extracted twice with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (230-400 silica gel,40-50% EtOAc: hexane) which gave methyl2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate (41.0g, 63%) as an off white solid.

Step 4:

To a stirred solution of methyl2-(4-fluorophenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate (13.0g, 36.2 mmol, 1.0 eq) in EtOH:THF (260:130 mL, 2:1), Raney Nickel (13.0g) was added and the reaction mixture was stirred under a hydrogenatmosphere for 16 h at RT. After completion of the reaction (monitoredby TLC), the reaction mixture was filtered through a celite bed and thecelite bed was washed 4-5 times with THF. The filtrate was concentratedto give methyl 2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (6.7 g,78%, syn:anti mixture) as a white solid.

Step 5:

To a stirred solution of methyl2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylate (10.0 g, 42.2 mmol,1.0 eq) in MeOH (200 mL) was added 2N NaOH solution (48 mL) and thereaction mixture was stirred at 80° C. for 16 h. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.1), thereaction mixture was concentrated and acidified with 2N HCl solution toobtain a solid which was filtered and washed with diethyl ether,followed by drying under vacuum to afford trans2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (6.4 g, 68%).

Step 6:

To a stirred solution of trans2-(4-fluorophenyl)-5-oxopyrrolidine-3-carboxylic acid (5.0 g, 22.4 mmol,1.00 eq) in toluene (50 mL) was added TEA (3.3 mL, 23.5 mmol, 1.05 eq)and DPPA (7.4 g, 26.9 mmol, 1.20 eq) and the reaction mixture was heatedto 90° C. for 30 min. Then benzyl alcohol (4.8 g, 44.8 mmol, 2.00 eq)was added and the reaction mixture was heated to reflux for 16 h. Aftercompletion (monitored by TLC), the reaction mixture was concentratedunder reduced pressure. The residue was then diluted with EtOAc (100mL), washed with water (2×100 mL), dried over Na₂SO₄ and finallyconcentrated under reduced pressure to get the crude product which waspurified by column chromatography (230-400 mesh silica gel; 0-2% MeOH inDCM) to afford trans-benzyl(2-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (4.1 g, 56%).

Step 7:

To a stirred solution of trans-benzyl(2-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)carbamate (2.0 g, 6.1 mmol, 1.0eq) in MeOH (50 mL) and THF (20 mL), Pd/C (0.3 g, 3.0 mmol, 0.5 eq) wasadded and the reaction was stirred with a hydrogen balloon for 2 h atRT. After completion (monitored by TLC), the reaction mixture wasfiltered through a celite bed and the celite bed was washed 2-3 timeswith THF. The filtrate was concentrated to get the desiredtrans4-amino-5-(4-fluorophenyl)pyrrolidin-2-one (1.1 g, 93%) as a browngum.

Synthesis of trans-4-amino-5-(2-methoxypyridin-4-yl)pyrrolidin-2-one(Intermediate A9)

Step 1:

Maleic anhydride (17.2 g, 175.0 mmol, 1.0 eq), p-thiocresol (21.7 g,175.0 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (29.2 g, 175.0 mmol, 1.0eq), and 2-methoxypyridine-4-carbaldehyde (24.0 g, 175.0 mmol, 1.0 eq)were taken up in 300 mL of toluene. The reaction mixture was refluxedfor 16 h with vigorous stirring. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.1), the reactionmixture was cooled to RT and the solvent was evaporated under reducedpressure to afford the crude1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid as a gummy liquid (80.0 g) which was used in the next step withoutfurther purification.

Step 2:

To a stirred solution of1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (57.0 g, 112.1 mmol, 1.0 eq) in acetone (300 mL), potassiumcarbonate (61.9 g, 448.3 mmol, 4.0 eq) and methyl iodide (28.0 mL, 448.3mmol, 4.0 eq) were added at 0° C., and the reaction was stirred at RTfor 16 h. After completion of the reaction (monitored by TLC, TLC system30% EtOAc in hexane, R_(f)-0.3), the solvent was removed under reducedpressure and the residue was partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(100-200 silica gel, 40% EtOAc in hexane) to afford methyl1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (35.0 g, 60%).

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(60.0 g, 114.8 mmol, 1.0 eq) in acetonitrile (300 mL), CAN (188.8 g,344.4 mmol, 3.0 eq) in water (300 mL) was added dropwise at 0° C.through an addition funnel and the reaction mixture was then stirred atRT for 16 h. After completion of the reaction (monitored by TLC, TLCsystem 70% EtOAc in hexane, Rf-0.3), the reaction mixture was dilutedwith water and extracted twice with EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The crude product was purified by column chromatography (230-400 silicagel, 40-50% EtOAc:hexane) to give methyl2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (12.0 g, 28%).

Step 4:

To a stirred solution of methyl2-(2-methoxypyridin-4-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(11.4 g, 30.6 mmol, 1.0 eq) in EtOH:THF (50:100 mL, 1:2), Raney Nickel(18 g) was added, and the reaction was stirred under a hydrogenatmosphere for 16 h at RT. After completion, (monitored by TLC, TLCsystem 70% EtOAc in hexane, Rf-0.4) the reaction mixture was filteredthrough a celite bed and the celite bed was washed 4-5 times with THF.The filtrate was concentrated to afford methyl2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate as a whitesolid (7.1 g, 93%, syn:anti mixture).

Step 5:

To a stirred solution of methyl2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylate (0.7 g, 2.8mmol, 1 eq) in MeOH (10 mL) was added 2N NaOH solution (6 mL) and thereaction mixture was stirred at 80° C. for 16 h. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.1), thereaction mixture was concentrated and acidified with 2N HCl solution toget a solid which was filtered off and was washed with diethyl ether.After drying under vacuumtrans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylic acid wasobtained (0.4 g, 61%).

Step 6:

To a stirred solution oftrans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidine-3-carboxylic acid (0.37g, 1.58 mmol, 1.00 eq) in toluene (20 mL) was added TEA (0.30 mL, 1.66mmol, 1.05 eq) and DPPA (0.40 mL, 1.89 mmol, 1.20 eq) and the reactionmixture was stirred at 90° C. for 30 min. Then benzyl alcohol (0.40 mL,3.16 mmol, 2.00 eq) was added to the reaction mixture and heated toreflux for 16 h. After completion, (monitored by TLC, TLC system 5% MeOHin DCM, Rf-0.3), the reaction mixture was concentrated under reducedpressure. The residue was then diluted with EtOAc (100 mL), washed withwater (2×100 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0-2% MeOH in DCM) to affordtrans-benzyl (2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)carbamate(0.20 g, 37%).

Step 7:

To a stirred solution of trans-benzyl(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)carbamate (0.2 g, 24.0mmol, 1.0 eq) in MeOH:THF (20 mL, 2:1), Pd/C (0.2 g, 10%, moist) wasadded and the reaction was stirred with a hydrogen balloon for 2 h atRT. After completion, (monitored by TLC, TLC system 5% MeOH in DCM,Rf-0.2), the reaction mixture was filtered through a celite bed and thecelite bed was washed 2-3 times with THF. The filtrate was concentratedto get trans-4-amino-5-(2-methoxypyridin-4-yl)pyrrolidin-2-one as abrown gum (0.1 g, 82%).

Synthesis of trans-4-amino-5-(o-tolyl)pyrrolidin-2-one (IntermediateA10)

Step 1:

Maleic anhydride (20.3 g, 208.2 mmol, 1.0 eq), p-thiocresol (25.8 g,208.2 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (34.7 g, 208.2 mmol, 1.0eq), and 2-fluorobenzaldehyde (25.0 g, 208.2 mmol, 1.0 eq) were taken upin 300 mL of toluene. The reaction mixture was refluxed for 16 h withvigorous stirring. After completion of the reaction (monitored by TLC,TLC system 5% MeOH in DCM, R_(f)-0.1), the reaction mixture was cooledto RT and the solvent was evaporated under reduced pressure to affordthe crude1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylicacid as a gummy liquid (101.0 g) which was used in the next step withoutfurther purification.

Step 2:

To a stirred solution of crude1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (101.0 g, 208.2 mmol, 1.0 eq) in acetone (1 L), potassium carbonate(115.0 g, 832.8 mmol, 4.0 eq) and methyl iodide (52.0 mL, 832.8 mmol,4.0 eq) were added at 0° C. and the reaction was stirred at RT for 16 h.After completion of the reaction (monitored by TLC, TLC system 30% EtOAcin hexane, R_(f)-0.3) the solvent was removed under reduced pressure andthe residue was partitioned between EtOAc and water. The aqueous layerwas extracted twice with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (100-200 silica gel, 40%EtOAc in hexane) to afford methyl1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylateas an off white solid (80.0 g, 76%).

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylate(80.0 g, 158.0 mmol, 1.0 eq) in acetonitrile (300 mL), CAN (260.0 g,475.0 mmol, 3.0 eq) in water (300 mL) was added dropwise to the reactionmixture at 0° C. through an addition funnel and the reaction mixture wasstirred at RT for 16 h. After completion of the reaction (monitored byTLC, TLC system 50% EtOAc in hexane, Rf-0.3), the reaction mixture wasdiluted with water and extracted twice with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(230-400 silica gel, 40-50% EtOAc: hexane) which gave methyl5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylate as an offwhite solid (21.5 g, 38%).

Step 4:

To a stirred solution of methyl5-oxo-2-(o-tolyl)-3-(p-tolylthio)pyrrolidine-3-carboxylate (21.5 g, 60.5mmol, 1.0 eq) in EtOH:THF (300:300 mL, 1:1), Raney Nickel (˜18 g) wasadded, and the reaction was stirred under a hydrogen atmosphere for 16 hat RT. After completion, (monitored by TLC, TLC system 70% EtOAc inhexane, Rf-0.4) the reaction mixture was filtered through a celite bedand the celite bed was washed 4-5 times with THF. The filtrate wasconcentrated to afford methyl 5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylateas a white solid (11.5 g, 82%, syn:anti mixture).

Step 5:

To a stirred solution of methyl5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylate (11.5 g, 49.3 mmol, 1.0 eq)in MeOH (400 mL) was added 2N NaOH solution (80 mL) and the reactionmixture was stirred at 80° C. for 16 h. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.1), the reactionmixture was concentrated and acidified with 2N HCl solution to get asolid which was filtered off and was washed with diethyl ether. Dryingunder vacuum then affordedtrans-5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylic acid (8.5 g, 79%).

Step 6:

To a stirred solution of trans-5-oxo-2-(o-tolyl)pyrrolidine-3-carboxylicacid (8.5 g, 38.0 mmol, 1.00 eq) in toluene (110 mL) were added TEA (5.5mL, 39.9 mmol, 1.05 eq) and DPPA (10.5 g, 45.0 mmol, 1.20 eq) and thereaction mixture was stirred at 90° C. for 30 min. After 30 min, benzylalcohol (8.4 g, 77.0 mmol, 2.00 eq) was added and the reaction mixturewas heated to reflux for 16 h. After completion (monitored by TLC, TLCsystem 5% MeOH in DCM, Rf-0.3), the reaction mixture was concentratedunder reduced pressure. The residue was then diluted with EtOAc (100mL), washed with water (2×100 mL), dried over anhydrous Na₂SO₄ and wasthen concentrated under reduced pressure to get the crude product whichwas purified by column chromatography (230-400 mesh silica gel; 0-2%MeOH in DCM) to afford trans-benzyl(5-oxo-2-(o-tolyl)pyrrolidin-3-yl)carbamate (8.0 g, 65%).

Step 7:

To a stirred solution of trans-benzyl(5-oxo-2-(o-tolyl)pyrrolidin-3-yl)carbamate (8.0 g, 24.0 mmol, 1.0 eq)in MeOH:THF (20 mL, 2:1), Pd/C (2.0 g, 10%, moist) was added, and thereaction mixture was stirred with a hydrogen balloon for 2 h at RT.After completion, (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.2),the reaction mixture was filtered through a celite bed and the celitebed was washed 2-3 times with THF. The filtrate was concentrated to getthe desired trans-4-amino-5-(o-tolyl)pyrrolidin-2-one as brown gum (4.5g, 99%).

Synthesis of trans-4-amino-5-(2-fluoro-5-methoxyphenyl)pyrrolidin-2-one(Intermediate A11)

Step 1:

Maleic anhydride (14.6 g, 149.7 mmol, 1.0 eq), p-thiocresol (18.5 g,149.7 mmol, 1.0 eq), 2,4-dimethoxy benzylamine (25.0 g, 149.7 mmol, 1.0eq), and 2-fluoro-5-methoxybenzaldehyde (23.0 g, 149.7 mmol, 1.0 eq)were taken up in 300 mL of toluene. The reaction mixture was refluxedfor 16 h with vigorous stirring. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, R_(f)-0.1), the reactionmixture was cooled to RT and the solvent was then evaporated underreduced pressure to afford the crude product as a gummy liquid (75.0 g,96%) which was used in the next step without further purification.

Step 2:

To a stirred solution of crude1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (75.0 g, 142.9 mmol, 1.0 eq) in acetone (1 L), potassium carbonate(78.9 g, 571.4 mmol, 4.0 eq) and methyl iodide (35.0 mL, 571.4 mmol, 4.0eq) were added at 0° C., and the reaction mixture was stirred at RT for16 h. After completion of the reaction (monitored by TLC, TLC system 30%EtOAc in hexane, R_(f)-0.3), the solvent was removed under reducedpressure and the residue was partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc. The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(100-200 silica gel, 40% EtOAc in hexane) to afford the desired methyl1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(45.0 g, 58%) as an off white solid.

Step 3:

To a stirred solution of methyl1-(2,4-dimethoxybenzyl)-2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(45.0 g, 83.5 mmol, 1.0 eq) in acetonitrile, CAN (137.3 g, 250.4 mmol,3.0 eq) in water was added dropwise through an addition funnel to thereaction mixture at 0° C. and the reaction mixture was stirred at RT for16 h. After completion of the reaction (monitored by TLC, TLC system 50%EtOAc in hexane, Rf-0.3), the reaction mixture was diluted with waterand extracted twice with EtOAc. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (230-400 silica gel,40-50% EtOAc: hexane) to give methyl2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(17.0 g, 52%) as an off white solid.

Step 4:

To a stirred solution of methyl2-(2-fluoro-5-methoxyphenyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(17.0 g, 43.7 mmol, 1.0 eq) in EtOH: THF (300:300 mL, 1:1), Raney Nickel(17 g) was added and the reaction mixture was stirred under a hydrogenatmosphere for 16 h at RT. After completion, (monitored by TLC, TLCsystem 70% EtOAc in hexane, Rf-0.4) the reaction mixture was filteredthrough a celite bed and the celite bed was washed 4-5 times with THF.The filtrate was concentrated to afford the desired methyl2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g, 77%,syn:anti mixture) as a white solid.

Step 5:

To a stirred solution of methyl2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylate (9.0 g, 33.7mmol, 1 eq) in MeOH (180 mL) was added 2 N NaOH solution (36 mL) and thereaction mixture was stirred at 80° C. for 16 h. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.1), thereaction mixture was concentrated and acidified with 2N HCl solution toobtain a solid which was filtered off and then washed with diethylether. Drying under vacuum affordedtrans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid(7.9 g, 93%).

Step 6:

To a stirred solution oftrans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic acid(7.9 g, 31.2 mmol, 1.00 eq) in toluene (80 mL) were added TEA (4.6 mL,32.8 mmol, 1.05 eq) and DPPA (10.3 g, 37.46 mmol, 1.20 eq) and thereaction mixture was stirred at 90° C. for 30 min. After 30 min, benzylalcohol (6.7 g, 62.4 mmol, 2.00 eq) was added and the reaction mixturewas heated to reflux for 16 h. After completion, (monitored by TLC, TLCsystem 5% MeOH in DCM, Rf-0.3), the reaction mixture was concentratedunder reduced pressure. The residue was then diluted with EtOAc (100mL), washed with water (2×100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to get the crude product which was purified bycolumn chromatography (230-400 mesh silica gel; 0-2% MeOH in DCM) toafford benzyl(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (1.5g, 13%).

Step 7:

To a stirred solution of benzyl(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (1.5g, 4.2 mmol, 1.0 eq) in MeOH: THF (20 mL, 2:1), Pd/C (0.3 g, 0.548 mmol,0.1 eq) was added, and the reaction mixture was stirred with a hydrogenballoon for 2 h at RT. After completion, (monitored by TLC, TLC system5% MeOH in DCM, Rf-0.2), the reaction mixture was filtered through acelite bed and the celite bed was washed 2-3 times with THF. Thefiltrate was concentrated to get the desiredtrans-4-amino-5-(2-fluoro-5-methoxyphenyl)pyrrolidin-2-one (0.9 g, 96%)as a brown gum.

Synthesis of tert-butyl(trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (IntermediateA12-Boc) and tert-butyl(cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (Intermediate A13-Boc)

Step 1:

To a stirred solution of 2-amino-2-cyclopropylacetic acid (40.0 g, 347.4mmol), 0.5N NaOH aqueous solution (240 mL) and 1,4-dioxane (200 mL) wasadded di-tert-butyl-di-carbonate (83.3 g, 382.1 mmol) at 0° C. Then thereaction mixture was allowed to warm up to ambient temperature and wasstirred for 16 h. The reaction mixture was acidified with 5% KHSO₄solution after completion of the reaction. The aqueous layer wasextracted with EtOAc, the combined organic layers were then washed withbrine, dried over sodium sulfate and concentrated under reduced pressureto afford 2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (40.0g) as a yellow sticky liquid.

Step 2:

To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-cyclopropylacetic acid (78.5 g, 365.1 mmol) and DCM (785 mL)were added Meldrum's acid (59.9 g, 401.6 mmol) and DMAP (62.4 g, 511.1mmol) at 0° C. The reaction mixture was allowed to stir at thistemperature for 30 min. To this reaction mixture was added EDC.HCl (98.0g, 511.1 mmol) and the reaction mixture was stirred at ambienttemperature for 12 h. The reaction mixture was diluted with EtOAc. Theorganic layer was washed with 5% citric acid, water and brine. Theorganic layer was then heated to 75° C. for 1 h, concentrated underreduced pressure. The obtained residue was triturated with diethyl etherto afford tert-butyl 2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate(33.1 g, 38%) as an off white solid.

Step 3:

To a stirred solution of tert-butyl2-cyclopropyl-3,5-dioxopyrrolidine-1-carboxylate (40.0 g, 167.3 mmol) in1,4-dioxane (200 mL) was added 1,4-dioxane-HCl (200 mL) at 0° C. Thereaction mixture was then stirred at ambient temperature for 3 h. Thereaction mixture was then concentrated under reduced pressure to afford5-cyclopropylpyrrolidine-2,4-dione (30.0 g) as an off white solid.

Step 4:

To a stirred solution of 5-cyclopropylpyrrolidine-2,4-dione (30.0 g,215.8 mmol) in a mixture of ethanol (270 mL) and acetic acid (30 mL) wasadded (4-methoxyphenyl)methanamine (29.6 g, 215.8 mmol) under nitrogenatmosphere. The reaction was then heated to 80° C. for 12 hours. Thereaction mixture was concentrated under reduced pressure, the obtainedresidue was basified with 1N NaOH, causing precipitation. Theprecipitated solid was filtered off and was then dried under reducedpressure to afford a light yellow solid.

¹H NMR (DMSO-d₆) δ: 7.17 (d, 2H), 6.98 (q, 1H), 6.83 (d, 2H), 6.66-6.58(m, 1H), 4.17 (s, 1h) 4.06 (d, 2H), 3.64 (s, 3H), 0.96 (td, 1H), 0.46(dq, 1H), 0.37 (p, 1H), 0.21 (dt, 1H), 0.12 (dd, 1H).

Step 5:

To a stirred solution of5-cyclopropyl-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrrol-2-one(17.0 g, 65.9 mmol) and acetic acid (170 mL) was added sodium cyanoborohydride (24.8 g, 395.3 mmol) at 0° C. and the reaction was stirredfor 1 h at this temperature. The reaction mixture was then concentratedunder reduced pressure; the obtained residue was basified with 1N NaOHand extracted with EtOAc. The combined organic layers were washed withwater and brine and were then dried over sodium sulfate and concentratedunder reduced pressure to get the crude product which was used in thenext step without further purification.

Step 6:

To a stirred solution of5-cyclopropyl-4-((4-methoxybenzyl)amino)pyrrolidin-2-one (3.8 g, 14.6mmol) and MeOH (38 mL) were added 2N HCl (4.0 mL), ammonium formate(18.4 g, 292.3 mmol) and 10% palladium on carbon (3.8 g) The reactionmixture was then heated to 80° C. for 12 h. The reaction mixture wasthen filtered through a celite bed and the filtrate was concentratedunder reduced pressure to afford 4-amino-5-cyclopropylpyrrolidin-2-one(5.8 g) as a yellow sticky solid.

Step 7:

To a stirred solution of trans-4-amino-5-cyclopropylpyrrolidin-2-one(5.8 g, 40.25 mmol) and DCM (25 mL) were added TEA (17.2 mL, 123.17mmol) and Boc anhydride (9.8 g, 45.17 mmol) at 0° C. The reactionmixture was then stirred at RT overnight. The reaction mixture was thendiluted with DCM. The organic layer was washed with water and brine,dried over sodium sulfate and concentrated under reduced pressure. Theobtained residue was purified by column chromatography using neutralaluminium oxide and 1% MeOH and CHCl₃ as an eluent to afford anoff-white solid which was further purified by preparative HPLC to affordtert-butyl (trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (0.42 g)and tert-butyl (cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate (1.4 g)as off-white solids.

tert-butyl (trans-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate(Intermediate C12-Boc)

¹H NMR (DMSO-d₆) δ: 7.78 (s, 1H), 7.20 (d, 1H), 3.87 (p, 1H), 2.79 (dd,1H), 2.46 (d, 1H), 2.01 (dd, 1H), 0.82 (dt, 1H), 0.38 (dd, 2H), 0.26(dd, 1H), 0.13-0.07 (m, 1H).

tert-butyl (cis-2-cyclopropyl-5-oxopyrrolidin-3-yl)carbamate(Intermediate C13-Boc)

¹H NMR (DMSO-d₆) δ: 7.84 (s, 1H), 7.25 (d, 1H), 4.18 (q, 1H), 2.88 (t,1H), 2.25 (d, 2H), 1.38 (s, 9H), 0.74 (dt, 1H), 0.38 (dt, 2H), 0.09 (d,2H).

Synthesis of tert-butyl((2R,3R)-2-(cyclopropylmethyl)-5-oxopyrrolidin-3-yl)carbamate(Intermediate C₁₋₄-Boc)

Step 1:

To a stirred solution of (R)-2-amino-3-cyclopropylpropanoic acid (20.0g, 154.9 mmol) in 1,4-dioxane (100 mL) was added 0.5N NaOH aqueoussolution (120 mL) and di-tert-butyl-di-carbonate (40.6 g, 185.8 mmol) at0° C., stirring was then continued at RT for 16 h. The solvent was thenconcentrated under reduced pressure, the resulting residue was acidifiedwith 2N HCl solution. The remains were extracted with EtOAc, washed withwater and brine. The organic layer was then dried over Na₂SO₄ andconcentrated in vacuo to afford(R)-2-((tert-butoxy-carbonyl)amino)-3-cyclopropylpropanoic acid as anoff white solid (25.0 g).

Step 2:

To a stirred solution of(R)-2-((tert-butoxycarbonyl)amino)-3-cyclopropylpropanoic acid (20.0 g,87.2 mmol) in DCM (200 mL) were added Meldrum's acid (13.8 g, 96.0 mmol)and DMAP (14.9 g, 122.1 mmol) at 0° C. After 30 min EDC.HCl (23.4 g,122.1 mmol) was added at 0° C., the reaction mixture was then allowed tostir at ambient temperature for 20 h. The reaction mixture was dilutedwith EtOAc (50 ml), washed with cold 5% KHSO₄ solution and brine. Theorganic layer was dried over Na₂SO₄ and the solvent was distilled offunder reduced pressure The remains were diluted with ethyl acetate (50mL), and were refluxed for 1 h at 65° C. Removal of the solvent underreduced pressure afforded tert-butyl(R)-2-(cyclopropylmethyl)-3-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate(27.0 g) as a yellow solid.

¹H NMR (DMSO-d₆) δ:12.3 (s, 1H), 6 8.31 (s, 1H), 6 4.89 (s, 1H),4.4-4.38 (m, 1H), 4.05-3.99 (m, 1H), 1.77-1.73 (m, 1H), 1.38 (s, 9H),0.45-0.44 (m, 1H), 0.23-0.22 (m, 2H), 0.2-0.1 (m, 2H).

Step 3:

To a stirred solution of tert-butyl(R)-2-(cyclopropylmethyl)-3,5-dioxopyrrolidine-1-carboxylate (10.0 g,65.4 mmol) in 1,4-dioxane (270 mL) was added 4M HCl in 1,4-dioxane (135mL) at 0° C. under a nitrogen atmosphere and the reaction mixture wasallowed to stir for 2 h at ambient temperature. The reaction mixture wasthen concentrated under vacuum and the obtained residue was trituratedwith diethyl ether to get (R)-5-(cyclopropylmethyl)pyrrolidine-2,4-dione(18.0 g) as a white gummy solid.

Step 4:

To a stirred solution of (R)-5-(cyclopropylmethyl)pyrrolidine-2,4-dione(10.0 g, 65.4 mmol) in EtOH:AcOH (100 mL, 9:1 w/v) was added(4-methoxyphenyl) methanamine (13.4 g, 98.0 mmol) at 0° C. and thereaction mixture was stirred to 80° C. under a nitrogen atmosphere for 1h. The reaction mixture was concentrated under reduced pressure and theobtained residue was triturated with 1N NaOH to get(R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrrol-2-one(5.0 g, 23%) as an off white solid.

Step 5:

To a stirred solution of(R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)-1,5-dihydro-2H-pyrrol-2-one(5.0 g, 18.4 mmol) in AcOH (50 mL) was added NaCNBH₃ (3.4 g, 55.1 mmol)at 0° C. and the reaction mixture was then stirred at ambienttemperature under a nitrogen atmosphere for 2 h. The reaction mixturewas then concentrated under reduced pressure. The obtained residue wasbasified with 1N NaOH at 0° C. leading to precipitation. The solid wasfiltered off and dried in vacuo to afford the crude product which waspurified by combiflash (using MeOH: DCM (0-5%)) to afford(4R,5R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)-amino)pyrrolidin-2-one(5.0 g).

Step 6:

To a solution of(4R,5R)-5-(cyclopropylmethyl)-4-((4-methoxybenzyl)amino)pyrrolidin-2-one(7.0 g, 25.5 mmol) in MeOH (210 mL), were added HCOONH₄ (32.1 g, 510.3mmol) and 10% Pd/C (7.0 g) at ambient temperature under a nitrogenatmosphere and the reaction mixture was then heated to 75° C. for 2 h.The reaction mixture was then filtered through celite and the obtainedfiltrate was concentrated under reduced pressure to afford(4R,5R)-4-amino-5-(cyclopropylmethyl)pyrrolidin-2-one (3.9 g).

Step 7:

To a solution of (4R,5R)-4-amino-5-(cyclopropylmethyl)pyrrolidin-2-one(3.9 g, 25.5 mmol) in DCM (39 mL), TEA (4.5 g, 44.6 mmol) and (Boc)₂O(6.1 g, 28.0 mmol) were added at 0° C. The mixture was stirred atambient temperature for 16 h, then the reaction mixture was diluted withDCM and washed consecutively with 5% citric acid solution and brine. Thesolvent was removed under reduced pressure to afford the crude productas an off white solid which was washed with diethyl ether (2×1 mL),filtered and the solid was dried in vacuo to afford tert-butyl((2S,3S)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamateas a white solid (2.6 g, 40%).

¹H NMR (DMSO-d₆) δ 7.8 (s, 1H), 7.3-7.2 (m, 1H), 4.26-4.21 (m, 1H)3.70-3.60 (m, 1H), 3.4 (s, 2H), 2.46-2.40 (m, 1H), 1.38 (s, 9H),0.45-0.44 (m, 1H), 0.23-0.22 (m, 2H), 0.20-0.10 (m, 2H).

Synthesis of (trans)-4-amino-5-(3,5-difluorophenyl)pyrrolidin-2-one(Intermediate A15)

Step 1:

A solution of 3,5-difluorobenzaldehyde (100.0 g, 0.7 mol, 1.0 eq),4-methyl-benzenethiol (87.4 g, 0.7 mol, 1 eq), maleic anhydride (69.0 g,0.7 mol, 1.0 eq) and ammonium acetate (54.2 g, 0.7 mol, 1.0 eq) intoluene (2.5 L) was stirred at ambient temperature for 2 hours, followedby heating to 140° C. in an autoclave for 16 hours. After completedisappearance of the starting material (monitored by LCMS), the reactionmixture was cooled to ambient temperature and was concentrated underreduced pressure to afford2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (266 g crude material) as a brown gum.

Step 2:

To a suspension of2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (266.0 g, 0.73 mol, 1.0 eq) in acetone (2.6 l) was added K₂CO₃(405.1 g, 2.93 mol, 4.0 eq) followed by methyl iodide (273.7 mL, 4.39mol, 6.0 eq) and the resulting suspension was stirred at ambienttemperature for 48 hours. The reaction mixture was then filtered and thefiltrate was concentrated under reduced pressure. The crude residue waspurified by column chromatography (silica 100-200 mesh and 40% ethylacetate/hexane as eluent) to afford2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (24.0 g, 9% over two steps) as a brown solid.

Step 3:

To a solution of2-(3,5-difluoro-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (20.0 g, 0.053 mol, 1.0 eq) in an ethanol:THF mixture(360 mL, 2:1) was added Raney Nickel (10 g). The resulting suspensionwas reacted in a Parr shaker at 40 psi of hydrogen pressure for 4 h.After completion of the reaction (monitored by LCMS), the reactionmixture was filtered over a bed of celite and the celite bed was washedwith ethanol (2×150 ml). The combined filtrates were concentrated underreduced pressure to afford 2-(3,5-difluoro-phenyl)-5-oxo-pyrrolidine-3carboxylic acid methyl ester (9 g crude material) as a brown gum.

Step 4:

To a suspension of2-(3,5-difluoro-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester(13.0 g, 0.05 mol, 1.0 eq) in MeOH (130 mL) was added 2N NaOH (75 mL,0.15 mol, 3.0 eq) at 0° C. and the resulting suspension was then stirredat 80° C. for 6 hours. After completion of the reaction (monitored byLCMS), the reaction mixture was concentrated and the residue was dilutedwith water and washed with ethyl acetate (2×150 ml). The aqueous basicmixture was acidified to pH 4 with 6N HCl. The precipitated solids werefiltered, dried and triturated with ethyl acetate and diethyl ether toafford trans-5-oxo-2-(3,5-difluorophenyl)pyrrolidine-3-carboxylic acid(4.1 g) as an off-white solid.

Step 5:

To a stirred solution oftrans-5-oxo-2-(3,5-difluorophenyl)pyrrolidine-3-carboxylic acid (4.6 g,0.019 mol, 1.0 eq) in a mixture of benzene (60 mL) and THF (23 mL) wasadded DPPA (5.43 ml, 0.025 mol, 1.3 eq) followed by DIPEA (4.96 ml,0.029 mol, 1.5 eq) at ambient temperature. The resulting reactionmixture was stirred at ambient temperature for 2 hours, followed by theaddition of benzyl alcohol (5.2 g, 0.048 mol, 2.5 eq) and the reactionmixture was heated at 90° C. for 16 hours. After completion of thereaction (monitored by TLC), the reaction mixture was concentrated. Thecrude residue was purified by column chromatography (silica 100-200mesh, 10% EA-Hexane as eluent), followed by trituration using MTBE toafford trans-benzyl(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)carbamate (intermediateA15-Cbz) (1.2 g, 18%) as an off-white solid.

Step 6:

Trans-benzyl-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)carbamate(611.0 mg, 1.764 mmol, 1.0 eq) was dissolved in EtOH/EtOAc/AcOH (35 mL,24/2/1, v/v/v) and is hydrogenated using a flow hydrogenation apparatus(Pd/C as catalyst, H₂ pressure below 10 bar). The inlet flask is rinsedrepeatedly with the solvent mixture described above. The solvent is thenremoved under reduced pressure, and the remains are purified using ionexchange chromatography (DSC-SCX).N-trans-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)amine (intermediateA15) is obtained in 99% yield (370.1 mg).

Synthesis of benzyl(trans-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (IntermediateA16-Cbz)

Step 1:

A solution of 3-methoxy-benzaldehyde (100.0 g, 0.73 mol, 1.0 eq),4-methyl-benzenethiol (91.2 g, 0.73 mol, 1.0 eq), maleic anhydride (72.0g, 0.73 mol, 1.0 eq) and ammonium acetate (56.2 g, 0.73 mol, 1.0 eq) inToluene (2.5 L) was stirred at ambient temperature for 2 hours, followedby heating to 140° C. in an autoclave for 16 hours. After completion ofthe reaction (monitored by LCMS), the reaction mixture was cooled toambient temperature and was concentrated under reduced pressure toafford2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (262 g crude material) as a brown gum.

Step 2:

To a suspension of2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid (262.0 g, 0.73, 1.0 eq) in acetone (2.6 L), was added K₂CO₃ (405.7g, 2.93 mol, 4.0 eq), followed by methyl iodide (274.1 mL, 4.40 mol, 6.0eq) and the resulting suspension was stirred at ambient temperature for48 hours. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography (silica 100-200 mesh and 15% ethyl acetate/hexaneas eluent) to afford2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (42.0 g, 15% over 2 steps) as a brown solid.

Step 3:

To a solution of2-(3-methoxy-phenyl)-5-oxo-3-p-tolylsulfanyl-pyrrolidine-3-carboxylicacid methyl ester (40.0 g, 0.053 mol, 1.0 eq) in an ethanol:THF mixture(670 mL, 2:1), was added Raney Nickel (40 g) and the resultingsuspension was stirred under hydrogen pressure (using a hydrogenballoon) for 16 hours. After completion of the reaction (monitored byLCMS), the reaction mixture was filtered over a bed of celite and thecelite bed was washed with ethanol (2×150 ml). The combined filtrateswere concentrated under reduced pressure to afford2-(3-methoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester(20.0 g, 77%) as a brown gum.

Step 4:

To a suspension of 2-(3-methoxy-phenyl)-5-oxo-pyrrolidine-3-carboxylicacid methyl ester (20.0 g, 0.08 mol, 1.0 eq) in MeOH (480 mL) was added2N NaOH (240 mL) at 0° C. and the resulting suspension was stirred at80° C. for 66 hours. After completion of the reaction (monitored byLCMS), the reaction mixture was concentrated and the residue was dilutedwith water and washed with ethyl acetate (2×250 mL). The basic aqueouslayer was acidified to pH 4 with 6N HCl. The precipitated solids werefiltered, dried, triturated with ethyl acetate and diethyl ether toafford trans-5-oxo-2-(3-methoxyphenyl)pyrrolidine-3-carboxylic acid (9.5g, 50%) as an off-white solid.

Step 5:

To a stirred solution oftrans-5-oxo-2-(3-methoxyphenyl)pyrrolidine-3-carboxylic acid (8.3 g,0.035 mol, 1.0 eq) in a mixture of benzene (250 mL) and THF (80 mL) wasadded DPPA (9.9 ml, 0.046 mol, 1.3 eq) followed by TEA (9.8 ml, 0.705mol, 20.0 eq) at ambient temperature. The resulting reaction mixture wasstirred at ambient temperature for 2 hours, then benzyl alcohol (4.8 ml,0.046 mol, 1.3 eq) was added and the reaction mixture was heated to 90°C. for 16 hours. After completion of the reaction (monitored by TLC),the reaction mixture was concentrated and the crude residue was purifiedby column chromatography (silica 100-200 mesh, 10% EA-Hexane as eluent),followed by trituration using MTBE to afford benzyl(trans-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-yl)carbamate (intermediateA16-Cbz) (5.6 g, 46%) as an off-white solid.

Synthesis of tert-butyl ((2R,3S)-2-benzyl-5-oxopyrrolidin-3-yl)carbamate(Intermediate A17-Boc ent1)

Step 1:

Benzaldehyde (150 g, 1.41 mol) was added to a stirred solution ofnitromethane (300 mL), acetic acid (20 mL) and ammonium acetate (11 g,0.14 mol) at ambient temperature under argon atmosphere. The solutionwas then heated to 110° C. for 4 h. The reaction mixture was then cooledand diluted with water (1000 mL) and extracted with EtOAc (3×500 mL).The combined organic layers were washed with water and brine. Theseparated organic layer was then concentrated to obtain the crudeproduct. This crude product was purified by column chromatography(silica gel, eluent EtOAc/hexane 5:95) to afford 130 g (62%) of(E)-(2-nitrovinyl)benzene as a pale yellow solid. (TLC system: 10% ethylacetate in pet-ether; Rf: 0.6).

Step 2:

To a stirred solution of NaBH₄ (43 g, 1.13 mol) in EtOH (300 mL) and1,4-dioxane (1000 mL) was added a solution of (E)-(2-nitrovinyl)benzenein 1,4-dioxane (1000 mL) at 0° C. The resulting reaction mixture wasstirred at ambient temperature for 30 minutes. The reaction mixture wasthen quenched with saturated NH₄Cl solution and the mixture was thenextracted with EtOAc (500 mL×3). The combined organic layers were washedwith brine (500 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated to obtain the crude product. This crudeproduct was purified by column chromatography (silica gel, eluentEtOAc/hexane 2:98) to afford 100 g (77%) of (2-nitroethyl)benzene as abrown liquid (TLC system: 5% ethyl acetate in pet-ether; Rf: 0.5).

Step 3:

To a stirred mixture of (2-nitroethyl)benzene (140 g, 0.927 mol) anddimethyl maleate (116 mL, 0.97 mol) was added TBAF.3H₂O (58 g, 0.185mol) at 0° C. The reaction mixture was then allowed to stir at 25° C.for 16 h. The reaction mixture was diluted with EtOAc (1000 mL), washedwith water and brine, dried over anhydrous Na₂SO₄, and concentratedunder reduced pressure to give a brown liquid. Flash columnchromatography of this material (eluent hexane/EtOAc 90:10) gavedimethyl 2-(1-nitro-2-phenylethyl)succinate (200 g, 73%) as a brownliquid. (TLC system: 30% ethyl acetate in pet-ether; Rf: 0.4).

Step 4:

To a stirred solution of dimethyl 2-(1-nitro-2-phenylethyl)succinate(100 g, 0.33 mol) in EtOAc (2 L), were added acetic acid (150 mL), water(50 mL) and zinc (110 g, 1.69 mol, lot wise). The reaction mixture washeated to 80° C. for 16 h. After completion of the reaction, thereaction mixture was cooled and filtered, and the filtrate was dilutedwith EtOAc and water. The layers were separated, and the separatedorganic layer was washed with water and sat. NaHCO₃ solution and wasthen concentrated under reduced pressure to give 50 g (65%) of methyl2-benzyl-5-oxopyrrolidine-3-carboxylate as a brown liquid. (TLC: 50%EtOAc in pet ether, Rf: 0.3).

Step 5:

To a stirred solution of methyl 2-benzyl-5-oxopyrrolidine-3-carboxylate(50 g, 0.214 mol) in methanol (500 mL) at ambient temperature was added2 N NaOH solution and the mixture was heated to reflux under N₂atmosphere for 24 h. The mixture was then concentrated under reducedpressure to give a residue, which was diluted with water (100 mL),acidified with sat. KHSO₄ solution and was then extracted with EtOAc(3×300 mL). The combined organic layers were washed with brine andconcentrated to give 38 g (82%) oftrans-2-benzyl-5-oxopyrrolidine-3-carboxylic acid as brown liquid. (TLCsystem: 20% MeOH/DCM; Rf: 0.1).

Step 6:

To a stirred solution of trans-2-benzyl-5-oxopyrrolidine-3-carboxylicacid (12 g, 54.79 mmol) in THF (120 mL) were added 50% T₃P (35 mL,54.79) and TEA (23 mL, 164.3 mmol) and the resulting mixture was stirredat ambient temperature for 10 min, prior to the addition of TMSN₃ (14.5mL, 109.56) and the resulting mixture was heated to reflux for 3 h. Thereaction mixture was cooled to ambient temperature, diluted with water(50 mL) and extracted with EtOAc (3×100 mL). The separated organic layerwas washed with brine and concentrated to give the crude product. Thiscrude product was purified by column chromatography (silicagel, eluentMeOH/CH₂C2 2:98) to afford 3.0 g (21%) of(trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamoyl azide as a brown solid(TLC system: 100% EA; Rf: 0.5).

Step 7:

A solution of (trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamoyl azide (3.0g, 11.58 mmol) in THF (30 mL) was added drop wise to 30 mL of 2 N NaOHsolution at 0° C. The resulting reaction mixture was stirred at ambienttemperature for 30 min and monitored by TLC, prior to the addition ofBoc anhydride (6 mL) at ambient temperature and the stirring wascontinued for 16 h. The reaction mixture was diluted with water (30 mL)and extracted with EtOAc (3×50 mL). The separated organic layer waswashed with brine and concentrated to give the crude product. The crudeproduct was triturated with 50% EtOAc in pet-ether to afford 2.1 g (63%)of tert-butyl (trans-2-benzyl-5-oxopyrrolidin-3-yl)carbamate as anoff-white solid which was separated by SFC to give individualenantiomers.

Chiral, preparative SFC was conducted as follows: column: Chiralpak IG(4.6×150 mm) 3 μm, co-solvent: methanol (40%), total flow: 3 g/minute,ABPR: 1500 psi, temperature 30° C. Retention times: enantiomer 1(intermediate A17-Boc ent1): 1.329 minutes, enantiomer 2: 1.965 minutes.

Synthesis of trans{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-yl}-carbamicacid benzyl ester (Intermediate A1-Cbz)

Step 1:

Benzyl N-[(3S)-2,5-dioxotetrahydrofuran-3-yl]carbamate (500.0 mg, 2.006mmol, 1.0 eq) was weighed out into a Schlenk flask, a stir bar wasadded, the flask was sealed and sparged with nitrogen. Then THF (20 mL)was added, followed by cooling of the reaction mixture to −78° C. Then,ethylmagnesiumbromide (3.2 mL of a 1 M solution in THF, 1.6 eq.) wasadded dropwise over two minutes, and the mixture was stirred at thattemperature for 2 hours. Then, 7 mL of 10% citric acid was added at −78°C. The mixture was allowed to warm to ambient temperature. Et₂O was thenadded as well as water. The layers were separated, and the aqueous layerwas extracted two more times with Et₂O. The combined organic layers werewashed with brine, dried over MgSO₄, and the solvent was removed underreduced pressure to yield a colorless oil (638 mg, containing3-(Benzyloxycarbonylamino)-4-oxo-hexanoic acid and byproducts) which wasused without further purification in the next step.

Step 2:

3-(Benzyloxycarbonylamino)-4-oxo-hexanoic acid (638 mg from step 1, usedcrude with all non-volatile byproducts) was dissolved in ethanol (20mL). A stir bar was added, the flask was sealed with a septum, and wassparged with nitrogen. The reaction mixture was cooled to 0° C. Then,thionyl chloride (0.14 mL, 1.9 mmol) was added, and the mixture wasstirred at ambient temperature for 16 hours. The solvent was evaporatedunder reduced pressure, and the crude material was then purified viasilica gel chromatography to yield 438.1 mg of a clear oil containingethyl 3-(((benzyloxy)carbonyl)amino)-4-oxohexanoate. The desiredcompound is accompanied by the an inseparable byproduct.

Step 3:

Sodium cyanoborohydride (53.8 mg, 0.855 mmol, 0.6 eq.) and ammoniumacetate (1099.0 mg, 14.250 mmol, 10.0 eq) were weighed out into a flask,a stir bar was added, the flask was sealed and sparged with nitrogen.Then, ethyl-3-(benzyloxycarbonylamino)-4-oxo-hexanoate (438 mg from step2, used crude with all non-volatile byproducts) in ethanol (5.0 mL) wasadded, and the mixture was heated to 50° C. for one hour. The solventwas then removed, and the remains were taken up in EtOAc and water. Thelayers were separated, and the aqueous phase was extracted two moretimes with EtOAc. The combined organic layers were then dried overMgSO₄, the solvent was removed and the crude material was purified viasilica gel chromatography to yield 125.0 mg (33%) of benzyl(2-ethyl-5-oxopyrrolidin-3-yl)carbamate.

Step 4:

Benzyl N-(2-ethyl-5-oxo-pyrrolidin-3-yl)carbamate (285.0 mg, 1.087 mmol,1.0 eq.), 1-(4-fluorophenyl)-5-iodo-indazole (404.1 mg, 1.120 mmol, 1.1eq.), K₃PO₄ (461.2 mg, 2.173 mmol, 2.0 eq.) and copper iodide (165.5 mg,0.869 mmol, 0.8 eq.) were weighed out into a microwave vial. A stir barwas added, the vial was sealed and sparged with nitrogen. Then,1,4-dioxane (10.8 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine(0.108 mmol, 15.4 mg, 0.1 eq.) were added and the mixture was stirred at90° C. for 16 hours. The reaction mixture was then cooled to ambienttemperature, sat. NaHCO₃ solution and DCM were added, and the mixturewas filtered through a hydrophobic frit. The organic solvent was thenremoved under reduced pressure, and the crude material was purified viasilica gel chromatography to yield 160.0 mg (31%) oftrans-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-yl}-carbamicacid benzyl ester and 70.0 mg (14%) ofcis-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-yl}-carbamicacid benzyl ester.

Synthesis of benzyl(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate(Intermediate A19-Cbz)

Step 1:

To a suspension of 5-chlorothiophene-2-carbaldehyde (60 g, 409.30 mmol),p-thiocresol (50.7 g, 409.30 mmol) and maleic anhydride (40.13 g, 409.30mmol) in toluene (1 L) was added (2,4-dimethoxyphenyl)methan-amine(68.81 g, 409.30 mmol) at ambient temperature. The resulting mixture wasrefluxed using a Dean-Stark trap for 16 h and was then concentrated. Thecrude product was purified via silica-gel (100-200 mesh) columnchromatography using 50% EtOAc in pet-ether as an eluent to afford 110 g(52%) of2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid as a brown solid (TLC system: EtOAc/pet ether (3:7), Rf: 0.1).

Step 2:

To a suspension of2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylicacid (95 g, 183.7 mmol) and K₂CO₃ (101.4 g, 735 mmol) in acetone (1.2 L)was added methyl iodide (47.4 mL, 735 mmol) at 0° C. The resultingmixture was allowed to stir at ambient temperature for 16 h, was thenfiltered and the filtrate was concentrated. The crude product waspurified via silica-gel (100-200 mesh) column chromatography using 5-10%EtOAc in pet-ether as an eluent to afford 79 g (81%) of methyl2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas a colorless gummy liquid (TLC system: EtOAc/pet ether (3:7), Rf0.44).

Step 3:

To a solution of methyl2-(5-chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(33 g, 62.14 mmol) in toluene (700 mL) were added AIBN (5.09 g, 31.07mmol) and tristrimethylsilyl silane (30.9 g, 124.29 mmol). The resultingmixture was refluxed for 16 h and was then concentrated. The crudeproduct was triturated with pet ether; the resulting solid was filteredoff and dried under vacuum to give 20 g (80%) of methyl2-(5-Chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylateas an off white solid (TLC system: EtOAc/pet ether (5:5), R_(f): 0.5).

Step 4:

A solution of methyl2-(5-Chlorothiophen-2-yl)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate(10 g, 24.44 mmol) in TFA (100 mL) was stirred at 80° C. for 16 h. Thereaction mass was concentrated. The residue was basified with sat.NaHCO₃ to pH 8, and extracted with EtOAc (2×500 mL). The combinedorganic layers were washed with brine (500 mL), dried over Na₂SO₄, andconcentrated. The residue was triturated with n-pentane to give 5 g ofcrude product of methyl2-(5-chlorothiophen-2-yl)-5-oxopyrrolidine-3-carboxylate as an off whitesolid (TLC system: EtOAc/pet ether (5:5), R_(f): 0.5).

Step 5:

A mixture of methyl2-(5-chlorothiophen-2-yl)-5-oxopyrrolidine-3-carboxylate (5 g, 19.3mmol) and 2 N NaOH (15 mL) in methanol (100 mL) was stirred at 80° C.for 4 h. The reaction mixture was then concentrated and triturated withdiethyl ether twice. The residue was taken up in cold water (100 mL) andacidified with 6 N HCl to pH 2 followed by extraction with EtOAc (2×500mL). The combined organic layers were then dried over Na₂SO₄ andconcentrated to afford 3.7 g (78%) oftrans-5-oxo-2-(5-chlorothiophen-2-yl)pyrrolidine-3-carboxylic acid as asolid (TLC system: EtOAc/pet-ether (6:4), R: 0.1).

Step 6:

To a solution oftrans-5-oxo-2-(5-chlorothiophen-2-yl)pyrrolidine-3-carboxylic acid (12g, 48.97 mmol) in benzene-THF (240 mL and 120 mL) were added DPPA (13.6mL, 63.66 mmol) and triethylamine (8.8 mL, 63.66 mmol). The resultingmixture was stirred at ambient temperature for 3 h, prior to theaddition of benzyl alcohol (6.6 mL, 63.66 mmol). The resulting mixturewas then heated to 80° C. for 16 h. The reaction mixture was cooled toambient temperature, diluted with water (500 mL) and extracted withEtOAc (2×500 mL). The combined organic layers were dried over Na₂SO₄ andconcentrated. The crude product was purified via silica-gel (100-200mesh) column chromatography using 40-50% EtOAc in pet-ether as an eluentto afford 6.3 g (36%) of benzyl(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate as anoff white solid (TLC system: EtOAc/pet-ether (6:4), Rf 0.4).

Synthesis oftrans-N-(1-(1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(Intermediate B1)

Step 1:

A stirred solution of intermediate A2 (1.2 g, 4.477 mmol, 1.0 eq),5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.8 g, 5.373 mmol, 1.2eq) and K₃PO₄ (1.9 g, 8.955 mmol, 2.0 eq) in 1,4-dioxane (20 mL) wasdegassed with argon for 30 min. Thentrans-N,N′-dimethylcyclohexane-1,2-diamine (0.3 g, 1.791 mmol, 0.4 eq)and CuI (0.2 g, 0.985 mmol, 0.2 eq) were added and the reaction mixturewas stirred for 16 h at 90° C. in a sealed tube. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.5), thereaction mixture was filtered through a celite bed and the celite bedwas washed 2-3 times with 1,4-dioxane. The combined organic layers wereconcentrated to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) to affordthe desiredtrans-2,2-difluoro-N-(5-oxo-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidin-3-yl)propanamide(1.5 g, 72%).

Step 2:

To a stirred solution oftrans-2,2-difluoro-N-(5-oxo-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyrrolidin-3-yl)propanamide(1.5 g, 3.20 mmol, 1.0 eq) in DCM (20 mL), TFA (15 mL) was added at 0°C. and the reaction was stirred for 16 h at ambient temperature. Aftercompletion of the reaction, (monitored by TLC, TLC system 5% MeOH inDCM, Rf-0.3), the reaction mixture was concentrated and basified withNaHCO₃ solution. The aqueous phase was extracted with DCM (3×100 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated to affordtrans-N-(1-(1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(1.1 g, 89%) as a solid.

Synthesis of 1-(4,4-difluorocyclohexyl)-5-iodo-1H-indazole (IntermediateC1)

To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.09 mmol, 1.0 eq)in THF (20 mL), DIAD (1.2 mL, 6.15 mmol, 1.5 eq) and Ph₃P (1.60 g, 6.15mmol, 1.5 eq) were added at 0° C. Then, 4,4-difluoro-cyclohexanol (0.84g, 6.15 mmol, 1.5 eq) was added at 0° C. and the reaction mixture wasstirred at ambient temperature for 16 h in the following. Aftercompletion of the reaction (monitored by TLC, TLC system 20% EtOAc inhexane, Rf-0.3), the reaction mixture was diluted with EtOAc (35 mL),washed with ice cold water (3×25 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to get the crude product as a mixture ofregioisomers which was purified and separated by column chromatography(230-400 mesh silica gel; 0 to 20% EtOAc in hexane) to afford1-(4,4-difluorocyclohexyl)-5-iodo-1H-indazole (0.10 g, 7%).

Synthesis of 1-cyclohexyl-5-iodo-1H-indazole (Intermediate C2)

Starting from cyclohexanol, intermediate C2 was synthesized in analogyto the synthetic procedure described for intermediate C1.

Synthesis of 1-(2-fluorobenzyl)-5-iodo-1H-indazole (Intermediate C3)

To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099 mmol, 1.0 eq)in THF (10 mL) NaH (0.24 g, 4.917 mmol, 1.2 eq) was added at 0° C. undera N₂ atmosphere. After 10 min, 1-(bromomethyl)-2-fluorobenzene (0.93 g,4.917 mmol, 1.2 eq) was added at ambient temperature. The reactionmixture was stirred for 1 h at ambient temperature. After completion ofthe reaction (monitored by TLC, 20% EtOAc in hexane, Rf-0.6) thereaction mixture was quenched with ice cold water (20 mL) and extractedwith EtOAc (3×20 ml), dried over Na₂SO₄ and was then concentrated underreduced pressure. The crude product was purified by columnchromatography (using 230-400 silica gel) to separate the two isomers.The major isomer was the desired 1-(2-fluorobenzyl)-5-iodo-1H-indazolewhich was confirmed by ¹H-NMR to afford intermediate C3 (0.57 g, 40%).

Synthesis of 1-(3-fluorobenzyl)-5-iodo-1H-indazole (Intermediate C4)

To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099 mmol, 1.0 eq)in THF (20 mL) NaH (0.24 g, 4.917 mmol, 1.2 eq) was added at 0° C. undera N₂ atmosphere. After 10 min, 1-(bromomethyl)-3-fluorobenzene (0.93 g,4.917 mmol, 1.2 eq) was added. The reaction mixture was stirred for 1 hat ambient temperature. After completion of the reaction (monitored byTLC, 20% EtOAc in hexane, Rf-0.6), the reaction mixture was quenchedwith ice cold water (20 mL) and extracted with EtOAc (3×20 ml), driedover Na₂SO₄ and was then concentrated. The crude product was purified bycolumn chromatography (using 230-400 silica gel) to separate the twoisomers. The major isomer was the desired1-(3-fluorobenzyl)-5-iodo-1H-indazole which was confirmed by ¹H-NMR toafford intermediate C4 (0.61 g, 42%).

Synthesis of 1-(4-fluorobenzyl)-5-iodo-1H-indazole (Intermediate C5)

To a stirred solution of 5-iodo-1H-indazole (1.00 g, 4.099 mmol, 1.0 eq)in THF (10 mL) NaH (0.24 g, 4.9174 mmol, 1.2 eq) was added at 0° C.under a N₂ atmosphere. After 10 min, 1-(bromomethyl)-4-fluorobenzene(0.93 g, 4.917 mmol, 1.2 eq) was added. The reaction mixture was stirredfor 1 h at ambient temperature. After completion of the reaction(monitored by TLC, 20% EtOAc in hexane, Rf-0.6), the reaction mixturewas quenched with ice cold water (20 mL) and extracted with EtOAc (3×20mL), dried over Na₂SO₄ and was then concentrated to give the crudeproduct which was purified by column chromatography (using 230-400silica gel) to separate the two isomers. The major isomer was thedesired 1-(4-fluorobenzyl)-5-iodo-1H-indazole which was confirmed by¹H-NMR to afford intermediate C5 (0.54 g, 37%).

Synthesis of 1-(cyclopropylmethyl)-5-iodo-1H-indazole (Intermediate C6)

To an ice cooled stirred solution of 5-iodo-1H-indazole (1.00 g, 4.09mmol, 1.0 eq) in DMF (20 mL), NaH (0.23 g, 4.91 mmol, 1.2 eq, 50% by wt)was added and the reaction mixture was stirred for 15 min.Bromomethyl-cyclopropane (0.43 ml, 4.50 mmol, 1.1 eq) was dissolved inDMF (10 mL) and was then added dropwise at 0° C. The reaction mixturewas then heated to 100° C. for 16 h. The reaction mixture was nextdiluted with EtOAc and washed with water. The combined organic layerswere concentrated under reduced pressure to get the crude product whichwas purified by column chromatography (100-200 mesh silica gel; 50%EtOAc/Hexane; R_(f)-value-0.5) to separate the two isomers. The majorisomer was the desired 1-(cyclopropylmethyl)-5-iodo-1H-indazole whichwas confirmed by ¹H-NMR to afford intermediate C6 (0.60 g, 50%).

Synthesis of 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole(Intermediate C7)

Step 1:

To a stirred solution of (4,4-difluorocyclohexyl)methanol (2.00 g,14.372 mmol, 1.0 eq) in DCM (20 mL), PBr₃ (1.63 mL, 17.247 mmol, 1.2 eq)was added at 0° C. and the reaction mixture was then stirred at ambienttemperature for 2 h. After completion of the reaction (monitored by TLC,TLC system 5% MeOH in DCM, Rf-0.3), the reaction was quenched withNaHCO₃ solution (150 mL), extracted with DCM (3×150 mL), dried overNa₂SO₄ and concentrated to get 4-(bromomethyl)-1,1-difluorocyclohexane(2.80 g, 96%).

Step 2:

To a stirred solution of 5-iodo-1H-indazole (0.83 g, 5.396 mmol, 0.8 eq)in DMF (15 mL) NaH (0.25 mg, 3.396 mmol, 1.2 eq, 50% by wt) was added at0° C., followed by the addition of4-(bromomethyl)-1,1-difluorocyclohexane (0.90 g, 4.245 mmol, 1.0 eq) andthe reaction mixture was stirred at ambient temperature for 16 h. Aftercompletion of the reaction (monitored by TLC, TLC system 5% MeOH/DCM,Rf-0.4), the reaction mixture was quenched with ice cold water (50 mL),extracted with EtOAc (3×50 mL), washed with brine (50 mL), dried overNa₂SO₄ and was then concentrated under reduced pressure to get the crudeproduct which was purified by column chromatography (230-400 mesh silicagel; 0 to 3% MeOH-DCM) to separate the two isomers. The major isomer wasthe desired 1-((4,4-difluorocyclohexyl)methyl)-5-iodo-1H-indazole whichwas confirmed by ¹H-NMR to afford intermediate C7 (0.54 g, 32%).

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine(Intermediate C8)

Step 1:

A mixture of 5-bromo-2-fluoro-pyridine-3-carbaldehyde (200.0 mg, 0.980mmol, 1.0 eq.) and (4-fluorophenyl)hydrazine hydrochloride (159.4 mg0.980 mmol, 1.0 eq.) in NMP (3.0 mL) was stirred at ambient temperaturefor two hours, before caesium carbonate (958.3 mg, 2.941 mmol, 3.0 eq.)was added and the mixture was heated to 115° C. for 1 hour. The mixturewas cooled to ambient temperature, and was diluted with water/EtOAc. Thelayers were separated, and the aqueous layer was extracted two moretimes with EtOAc. The combined organic layers were then washed withbrine and were dried over MgSO₄. The solvent was removed under reducedpressure and the remains were purified using silica gel chromatographyto obtain 184.4 mg (64%) of5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine.

Synthesis of 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine(Intermediate C9)

5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine was prepared inanalogy to 5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine, using2-bromo-5-fluoroisonicotinaldehyde instead of5-bromo-2-fluoro-pyridine-3-carbaldehyde. Yield: 47%

Synthesis of(trans)-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(Intermediate D1)

Step 1:

To a stirred solution of furan-2,5-dione (2.98 g, 30.46 mmol, 1.0 eq),4-methylbenzenethiol (3.78 g, 30.46 mmol, 1.0 eq) and2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (5.00 g, 30.46 mmol, 1.0eq) in dry toluene (100 mL) was added benzyl amine (3.25 g, 30.46 mmol,1.0 eq) at ambient temperature under a N₂ atmosphere and the reactionmixture was stirred at 111° C. for 24 hours. After completion of thereaction (monitored by TLC), the solvent was removed in vacuo and theresidue was dissolved in acetone (100 mL), followed by the addition ofK₂CO₃ (16.81 g, 121.83, mmol, 4.0 eq) and methyl iodide (17.29 g, 121.83mmol, 4.0 eq) at 0° C. The reaction mixture was slowly warmed to ambienttemperature and was stirred overnight. After the solvent was removedunder reduced pressure, water was added and extraction with EtOAc wasperformed. The organic layer was washed with water and brine, dried overNa₂SO₄ and concentrated under reduced pressure. The crude residue waspurified by column chromatography (silicagel, 10-50% EtOAc in hexane) toafford methyl1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylateas a pale yellow liquid. (3.0 g, 21%).

Step 2:

To a stirred solution of methyl1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxo-3-(p-tolylthio)pyrrolidine-3-carboxylate(7.0 g, 14.31 mmol, 1.0 eq) in a 1:2 mixture of THF:EtOH (656 mL) wasadded Raney Nickel (49.0 g) at room temperature under a N₂ atmosphereand the reaction mixture was stirred at ambient temperature for 48hours. The reaction mixture was filtered through celite, and the solventwas removed in vacuo. The reaction mixture was then diluted with waterand extracted with EtOAc. The organic layer was washed with water andbrine, dried over Na₂SO₄ and concentrated under reduced pressure toafford the product as a racemic mixture ofmethyl-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylateas a white solid. (5.0 g, 53%).

Step 3:

To a stirred solution ofmethyl-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidine-3-carboxylate(12.0 g, 32.66 mmol, 1.0 eq) in a 1:1 mixture of t-butyl alcohol and THF(1.2 L), was added KOtBu (1.1 g, 10.19 mmol, 0.3 eq) at room temperatureunder N₂ atmosphere and then the reaction mixture was stirred at ambienttemperature overnight. The solvent was then removed in vacuo, and thecrude product was used in the next step without purification. (Yield: 12g crude material).

Step 4:

To a stirred solution of methyltrans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxylate(5.0 g, 8.98 mmol, 1.0 eq) in MeOH (50 mL), IM LiOH (15.71 ml, 15.72mmol, 1.75 eq) was added at room temperature under a N₂ atmosphere andthen the reaction mixture was stirred at room temperature for 6 hours.After completion of the reaction (monitored by TLC), the solvent wasremoved in vacuo. The reaction mixture was cooled to 0° C. and dilutedwith water. Adjustment of the pH to 4 with 1N HCl, caused a solid toslowly precipitate out. This precipitate was filtered and dried in vacuoto affordtrans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxylicacid as a white solid. (3.3 g).

Step 5:

To a stirred solution oftrans-5-oxo-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrrolidine-3-carboxylicacid (8.0 g, 22.64, mmol, 1.0 eq) in t-BuOH (50.3 g, 679.17 mmol, 30.0eq), TEA (2.7 g, 27.17 mmol, 1.2 eq) and DPPA (7.5 g, 27.17 mmol, 1.2eq) were added at 0° C. under a N₂ atmosphere and then the reactionmixture was stirred at 82° C. for 1 hour, followed by heating to 100° C.for 5 hours. The reaction progress was monitored by TLC and uponcompletion, the solvent was removed in vacuo. The reaction mixture wascooled to ambient temperature, diluted with saturated NaHCO₃ andextracted with EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄ and concentrated under reduced pressure. The cruderesidue was purified using column chromatography (silicagel, 10-40%EtOAc in hexane) to afford tert-butyl((trans)-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamateas a white solid. (6.0 g, 63%).

Step 6:

In a round-bottom flask containing tert-butyl((trans)-1-benzyl-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(2.0 g, 4.71 mmol, 1.0 eq) in dry THF (81.4 ml), anhydrous ammonia wascondensed at −70° C., sodium (2 g) was added to the reaction mixture.Stirring was continued at the same temperature for 30 minutes. At −70°C., solid NH₄Cl was added to the reaction mixture, which was then slowlywarmed to 0° C. The residue was treated with saturated NH₄Cl solution,warmed to room temperature and extracted with dichloromethane (3×30 mL).The organic extracts were dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silicagel, 0-70% EtOAc in hexane) to afford tert-butyl((trans)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamateas a white solid (0.65 g, 41%).

Step 7:

To a sealed vial containing tert-butyl((trans)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(100 mg, 0.30 mmol, 1.00 eq), 2,2′-bipyridyl (33 mg, 0.21 mmol, 0.70 eq)and potassium phosphate (130 mg, 0.60 mmol, 2.00 eq) were addeddimethylsulfoxid (2.1 mL) and 1-(4-fluorophenyl)-5-iodo-indazole (150mg, 0.45 mmol, 1.50 eq) and the mixture was degassed under a nitrogenatmosphere. After ca. 2 min, copper(I)iodide (2.3 mg, 0.01 mmol, 0.04eq) was added and the sealed vial was degassed once more. The resultingmixture was stirred overnight at 110° C. Then, DCM and a saturatedsodium bicarbonate solution were added, the phases were separated via ahydrophobic frit, and the organic solvent was removed under reducedpressure. The crude residue was purified by column chromatography,followed by preparative HPLC to afford tert-butyl((trans)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(22 mg, 13%).

Step 8:

A solution of tert-butyl((trans)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-oxopyrrolidin-3-yl)carbamate(21.0 mg, 0.039 mmol, 1.0 eq) in ethanol (0.45 ml) was cooled to 0° C.,and acetylchloride (0.014 mL, 0.193 mmol, 5.0 eq) was added dropwise.Then, the ice bath was removed, and the reaction mixture was stirred at40° C. for 3 hours. Then, the mixture was allowed to cool to ambienttemperature, and was stirred overnight. The solvent was then removedunder reduced pressure to yield crude(trans)-4-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(Intermediate D1, 15.0 mg, 81%).

Synthesis of(trans)-4-Amino-1-[1-(4-fluoro-phenyl)-1H-indazol-5-yl]-5-phenyl-pyrrolidine-2-one(Intermediate D2)

Step 1:

To a stirred solution of benzylN-[(trans)-2-phenyl-5-oxo-pyrrolidin-3-yl]carbamate (intermediateA2-Cbz)(1.0 g, 3.22 mmol, 1.0 eq) and1-(4-fluoro-phenyl)-5-iodo-1H-indazole (1.1 g, 3.22 mmol, 1.0 eq) in1,4-dioxane (80 mL) in a sealed tube was added potassium phosphate (1.4g, 6.44 mmol, 2.0 eq) followed bytrans-N,N′-dimethylcyclohexane-1,2-diamine (1.02 ml, 0.644 mmol, 0.2eq). The reaction mixture was degassed under an argon atmosphere for 30minutes. CuI (61.3 mg, 0.322 mmol, 0.1 eq) was added and the reactionwas heated to 90° C. for 16 hours (monitored by LCMS). The reactionmixture was filtered through a bed of celite and the celite bed waswashed with ethyl acetate (500 mL), the combined filtrate wasconcentrated under reduced pressure and was purified by columnchromatography (100-200 silica gel, 30-40% ethyl acetate-hexane aseluent) to afford trans{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl}-carbamicacid benzyl ester (0.70 g, 42%)

Step 2:

To a stirred solution of trans{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl}-carbamicacid benzyl ester (18.0 g, 34.58 mmol) in THF (800 mL) was added 10%Pd/C (50% moist, 40 g) and the reaction mixture was then stirred under aH₂ balloon until completion (monitored by TLC). The reaction mixture wasfiltered through a celite bed and the celite bed was washed with THF.The filtrate was concentrated and triturated with DCM-pentane to affordtrans4-amino-1-[1-(4-fluoro-phenyl)-1H-indazol-5-yl]-5-phenyl-pyrrolidine-2-oneas an off-grey solid (10.8 g, 81%).

The racemic intermediate D2 can be separated by chiral HPLC using thefollowing conditions: column: CHIRALPAK AD-H (4.6×2500) mm, mobilePhase: MeOH (100%), temperature: 40° C.

Using those conditions, intermediate D2-ent1 (retention time: 6.15minutes) and intermediate D2-ent2 (retention time: 9.31 minutes) can beobtained.

Synthesis of(trans)-4-amino-5-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(Intermediate D6)

Step 1:

(2,4-dimethoxyphenyl)methylN-[(trans)-2-(3-chlorophenyl)-5-oxo-pyrrolidin-3-yl]carbamate(intermediate A1′, 500 mg, 1.235 mmol, 1.00 eq),1-(4-fluorophenyl)-5-iodo-indazole (438 mg, 1.297 mmol, 1.05 eq),potassium phosphate (524 mg, 2.470 mmol, 2.00 eq) and CuI (12 mg, 0.062mmol, 0.05 eq) were weighed into a vial. The reaction mixture was thendegassed under a nitrogen atmosphere. Then, 1,4-dioxane (5 mL) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (14 mg, 0.124 mmol, 0.1 eq)were added, and the reaction mixture was heated to 115° C. overnight.The reaction mixture was filtered through a bed of celite and the celitebed was washed with DCM and the combined filtrates were concentratedunder reduced pressure. The crude residue was purified by columnchromatography (silicagel, cHex/EtOAc) to afford trans{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-(3-chlorophenyl)pyrrolidin-3-yl}-carbamicacid 2,4-dimethoxybenzyl ester (590 mg, 78%).

Step 2:

A solution of trans{l-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-(3-chlorophenyl)pyrrolidin-3-yl}-carbamicacid 2,4-dimethoxybenzyl ester (590 mg, 0.959 mmol, 1.0 eq) was stirredat ambient temperature. After completion of the reaction (monitored byLCMS), the reaction mixture is cooled to 0° C. and was quenched withsaturated sodium bicarbonate solution. Extraction with DCM is thenfollowed by washing of the combined organic layers with saturated sodiumbicarbonate solution and drying over magnesium sulfate. Afterfiltration, the solution is concentrated under reduced pressure toafford(trans)-4-amino-5-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(intermediate D6, 338 mg, 84%).

Synthesis of(4S,5R)-4-amino-5-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(Intermediate D8)

Step 1:

Tert-butyl ((2R,3S)-2-benzyl-5-oxopyrrolidin-3-yl)carbamate (300 mg,1.033 mmol, 1.0 eq.), 1-(4-fluorophenyl)-5-iodo-indazole (366.8 mg,1.085 mmol, 1.05 eq.), K₃PO₄ (438.6 mg, 2.066 mmol, 2.0 eq.) copperiodide (157.4 mg, 0.826 mmol, 0.8 eq.) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (14.7 mg, 0.103 mmol, 0.1eq.) were weighed out into a microwave vial. A stir bar was added, thevial was sealed and sparged with nitrogen. Then, 1,4-dioxane (5.2 mL)was added, and the mixture was heated to 100° C. for 22 hours undermicrowave irradiation. Then, the temperature was raised to 120° C. for16 hours. The reaction mixture was cooled to ambient temperature, andsat. NaHCO₃ solution and DCM were added. The mixture was filteredthrough a hydrophobic frit, and the organic solvent was then evaporated.The crude remains were purified using silica gel chromatography to yield180.0 mg (35%) of tert-butyl((2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)carbamate.

Step 2:

Tert-butyl((2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)carbamate(180.0 mg, 0.360 mmol, 1.0 eq.) was dissolved in ethanol (3.6 mL) andthe mixture was cooled to 0° C. Then, acetyl chloride (0.26 mL, 3.596mmol, 10 eq.) was added, and the reaction mixture was stirred at ambienttemperature for 16 hours. Then, acetyl chloride (0.26 mL, 3.596 mmol, 10eq.) and a drop of water were added, and the mixture was stirred foranother 24 hours. The reaction mixture was then evaporated to dryness toyield 93.0 mg (53%) of(4S,5R)-4-amino-5-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(intermediate D8).

Synthesis ofcis-4-amino-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-oneIntermediate D9)

Step 1:

Cis-5-(Cyclopropylmethyl)-4-((4-methoxybenzyl)amino)pyrrolidin-2-one(200.0 mg, 0.729 mmol, 1.0 eq.), 5-bromo-1-(4-fluorophenyl)indazole(318.3 mg, 1.093 mmol, 1.5 eq.), caesium carbonate (475.0 mg, 1.458mmol, 2.0 eq.), Xantphos (63.2 mg, 0.109 mmol, 0.15 eq.), and Pd₂dba₃(33.3 mg, 0.036 mol, 0.05 eq.) were weighed out into a microwave vial, astir bar was added, the vial was sealed and purged with nitrogen.1,4-dioxane (7.5 mL) was then added, and the mixture was heated to 90°C. for 48 h. The reaction mixture was then cooled to ambienttemperature, was then filtered and the solvent was removed under reducedpressure. The crude remains were then purified via silica gelchromatography to yield 150.0 mg ofcis-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((4-methoxybenzyl)amino)pyrrolidin-2-one.

Step 2:

Cis-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-4-((4-methoxybenzyl)amino)-pyrrolidin-2-one(118.0 mg, 0.244 mmol, 1.0 eq.) was dissolved in ethanol (23.6 mL) andethyl acetate (23.6 mL). The mixture was then hydrogenated using flowhydrogenation (up to 10 bar H₂-pressure). The remains were evaporated todryness to obtain 81.8 mg (92%) ofcis-4-amino-5-(cyclopropylmethyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(intermediate D9).

The intermediates in Table 1 were synthesized in analogy to the examplesdescribed above, using the starting material specified below.

Intermediate Structure In analogy to Starting material Intermediate D3

Intermediate D2 intermediate A16- Cbz Intermediate D4

Intermediate D2 intermediate A8- Cbz Intermediate D5

Intermediate D2 intermediate A5-Cbz Intermediate D7

Intermediate D1 Intermediate A12- Boc

EXAMPLE 1:N-(TRANS-2-(2,3-DIHYDROBENZO[B][1,4]DIOXIN-6-YL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

2,2-difluoropropanoic acid (8.6 mg, 0.078 mmol, 2.0 eq) was weighed outinto a vial, followed by the addition of(trans)-4-amino-5-(2,3-dihydrobenzo[b][,4]dioxin-6-yl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)pyrrolidin-2-one(intermediate D1, 19.0 mg, 0.039 mmol, 1.0 eq) in dichloromethane (0.19mL), followed by the addition of triethylamine (0.011 mL, 0.078 mmol,2.0 eq) at ambient temperature. Propylphosphonic anhydride solution (≥50wt. % in ethyl acetate, 0.046 mL, 0.078 mmol, 2.0 eq) was then added,and the reaction mixture was stirred overnight. After 16 hours, thereaction mixture was diluted with sat. NaHCO₃ solution and DCM. Theresulting mixture was stirred for another 30 minutes, before beingfiltered through a hydrophobic frit. The solvent was removed underreduced pressure and the residue was purified by column chromatographyand later HPLC to give example 1 (14.0 mg, 67%).

¹H NMR (DMSO-d₆) δ: 9.43 (d, 1H), 8.32 (d, 1H), 7.89 (d, 1H), 7.78-7.74(m, 2H), 7.73 (d, 1H), 7.64 (dd, 1H), 7.46-7.35 (m, 2H), 6.87-6.74 (m,3H), 5.22 (d, 1H), 4.30-4.20 (m, 1H), 4.19-4.15 (m, 4H), 3.09 (dd, 1H),2.60 (dd, 1H), 2.07 (s, 1H), 1.79 (t, 3H).

EXAMPLE 2:2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE

Step 1:

To a stirred solution of intermediate A2 (1.0 g, 5.68 mmol, 1.0 eq) inDMF (20 mL), HATU (3.2 g, 8.52 mmol, 1.5 eq), DIPEA (4.9 mL, 28.40 mmol,5.0 eq) and 2,2-difluoro-propionic acid (0.8 g, 7.38 mmol, 1.3 eq) wereadded. The reaction mixture was then stirred for 16 h at ambienttemperature. After completion, the reaction mixture was diluted withEtOAc and was washed with ice cold water, sat. NaHCO₃ and sat. NH₄Clsolution. The combined organic layers were concentrated under reducedpressure to get the crude product which was purified by columnchromatography (100-200 mesh silica gel; 2% MeOH-DCM; R_(f)-value-0.5)to affordtrans-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide (1.4 g,93%).

Step 2:

A stirred solution oftrans-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide (0.50 g,1.86 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.75 g, 2.23mmol, 1.2 eq) and K₃PO₄ (0.79 g, 3.73 mmol, 2.0 eq) in 1,4-dioxane (20mL) was degassed with argon for 15 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.10 g, 0.75 mmol, 0.4 eq)and CuI (0.07 g, 0.37 mmol, 0.2 eq) were added and the reaction wasstirred for 16 h at 90° C. After completion, the reaction mixture wasfiltered through a celite bed and the celite bed was washed 2-3 timeswith EtOAc. The combined organic layers were concentrated to get thecrude product which was purified by column chromatography (100-200 meshsilica gel; 50% EtOAc-Hexane; R_(f)-value-0.5) to afford the racemicproduct. Further enantiomer separation was done by chiral preparativeHPLC to afford2,2-difluoro-N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)propanamide(0.06 g; RT=4.32 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min)and2,2-difluoro-N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)propanamide(0.05 g; RT=5.20 min; Column Nam: Chiralpak IA (250×4.6 mm) 5 μm, MobilePhase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ:9.48 (d, 1H), 8.30 (d, 1H), 7.88 (d, 1H), 7.76-7.72(m, 2H), 7.71 (d, 1H), 7.64 (dd, 1H), 7.42-7.34 (m, 4H), 7.32 (t, 2H),7.26-7.22 (m, 1H), 5.32 (d, 1H), 4.34-4.25 (m, 1H), 3.11 (dd, 1H), 2.64(dd, 1H), 1.79 (t, 3H).

EXAMPLE 4:2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-2-(2-METHOXYPYRIDIN-4-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Step 1:

To a stirred solution of 2,2-difluoropropanoic acid (0.64 g, 5.79 mmol,1.2 eq) in DMF (10 mL) HATU (3.60 g, 9.65 mmol, 2.0 eq), DIPEA (4.2 mL,24.13 mmol, 5.0 eq) and intermediate A9 (1.00 g, 4.83 mmol, 1.0 eq) wereadded at 0° C. and the reaction mixture was then stirred at ambienttemperature for 16 h. After completion of the reaction (monitored byTLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction mixture wasdiluted with EtOAc (25 mL), washed with ice cold water (3×25 mL), driedover Na₂SO₄ and concentrated to get the crude product which was purifiedby column chromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) toaffordtrans-2,2-difluoro-N-(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide(0.76 g, 52%).

Step 2:

A stirred solution oftrans-2,2-difluoro-N-(2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide(0.378 g, 1.263 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.512 g, 1.515 mmol, 1.2 eq) and K₃PO₄ (0.535 g, 2.526 mmol, 2.0 eq) in1,4-dioxane (25 mL) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.071 g, 0.505 mmol, 0.4 eq)and CuI (0.048 g, 0.253 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM,Rf-0.1), the reaction mixture was filtered through a celite bed and thecelite bed was washed 2-3 times with dioxane. The combined organiclayers were concentrated under reduced pressure to get the crude productwhich was purified by column chromatography (230-400 mesh silica gel; 0to 6% MeOH in DCM) to afford the racemic product. Further enantiomerseparation was done by preparative chiral HPLC to afford pure2,2-difluoro-N-((2S,3R)-1-(1(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide(0.057 g, RT=6.16 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)and2,2-difluoro-N-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)propanamide(0.047 g, RT=6.89 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 9.51-9.49 (m, 1H), 8.32 (s, 1H), 8.09 (d, 1H), 7.89(s, 1H), 7.77-7.72 (m, 3H), 7.67-7.64 (m, 1H), 7.42-7.37 (m, 2H), 7.00(d, 1H), 6.76 (s, 1H), 5.33-5.32 (m, 1H), 4.31-4.29 (m, 1H), 3.76 (s,3H), 3.14-3.07 (m, 1H), 2.67-2.62 (m, 1H), 1.84-1.74 (m, 3H).

EXAMPLE 5:N-(TRANS-2-(2,4-DIFLUOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

A solution of intermediate A3 (0.85 g, 4.09 mmol, 1.0 eq) in DMF (12 mL)was treated with 2,2-difluoropropanoic acid (0.57 g, 5.21 mmol, 1.3 eq)in the presence of HATU (3.04 g, 8.01 mmol, 2.0 eq) and DIPEA (3.5 mL,20.04 mmol, 2.0 eq) and this mixture was stirred at ambient temperaturefor 16 h. After ensuring complete consumption of starting material asevident from LCMS, the reaction mixture was partitioned between EtOAcand water. The organic extracts were washed with brine, dried andconcentrated under reduced pressure to afford the crude product whichwas purified by flash column chromatography (230-400 mesh silica gel; 5%MeOH/EtOAc; R_(f)-value-0.4) to affordN-(trans-2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.70 g, 58%) as an off white solid.

Step 2:

To a stirring solution ofN-(trans-2-(2,4-difluorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.25 g, 0.82 mmol, 1.0 eq) and 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.28 g, 0.82 mmol, 1.0 eq) in 1,4-dioxane (4 mL), K₃PO₄ (0.35 g, 1.64mmol, 2.0 eq), CuI (0.03 g, 0.16 mmol, 0.2 eq) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (0.05 g, 0.32 mmol, 0.4 eq)were added at ambient temperature under a nitrogen atmosphere and themixture was degassed with a stream of nitrogen for 5 min. The resultingmixture was then heated to 90° C. for 16 h. The reaction mixture wasthen allowed to cool to ambient temperature, was filtered andconcentrated to afford the crude product which was purified by flashcolumn chromatography (230-400 mesh silica gel; 5% MeOH/EtOAc;R_(f)-value-0.4) to affordN-(trans-2-(2,4-difluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.15 g, 36%) as an off white solid.

¹H NMR (DMSO-d₆) δ: 9.42 (d, 1H), 8.33 (s, 1H), 7.8 (d, 1H), 7.76-7.71(m, 3H), 7.51-7.45 (m, 2H), 7.4 (t, 2H), 7.22-7.17 (m, 1H), 7.02-6.98(m, 1H), 5.50 (d, 1H), 4.49 (m, 1H), 3.15-3.08 (m, 1H), 2.70 (dd, 1H),1.76 (t, 3H).

EXAMPLE 6:N-(TRANS-1-(1-(3,4-DIFLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

To a stirred solution of intermediate B1 (0.200 g, 0.521 mmol, 1.0 eq),(3,4-difluorophenyl)boronic acid (0.165 g, 1.042 mmol, 2.0 eq) andpyridine (0.1 mL, 1.042 mmol, 2.0 eq) in DCM (20 mL), was added Cu(OAc)₂(0.142 g, 0.781 mmol, 1.5 eq) and the reaction mixture was stirred for16 h at ambient temperature. After completion of the reaction (monitoredby TLC, TLC system 5% MeOH in DCM, Rf-0.4), the solvent was removedunder reduced pressure, and the residue was partitioned between DCM andwater. The aqueous layer was extracted twice with DCM (2×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude product was purified by preparativeHPLC to affordN-(trans-1-(1-(3,4-difluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(0.051 g, 20%).

¹H NMR (DMSO-d₆) δ: 9.50-9.49 (m, 1H), 8.34 (s, 1H), 7.89-7.87 (m, 3H),7.67-7.60 (m, 3H), 7.36-7.23 (m, 5H), 5.32 (s, 1H), 4.29-4.25 (m, 1H),3.14-3.07 (m, 1H), 2.65-2.60 (m, 1H), 1.83-1.73 (m, 3H).

EXAMPLE 9:N-TRANS-(1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)CYCLOPROPANESULFONAMIDE

N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)amine(intermediate D2, 144.0 mg, 0.373 mmol, 1.0 eq) was dissolved in DCM(2.0 mL), and the solution was cooled to 0° C. Triethylamine (0.31 mL,2.236 mmol, 6.0 eq) was then added, followed by the dropwise addition ofcyclopropanesulfonyl chloride (0.15 mL, 1.491 mmol, 4.0 eq). Thereaction mixture was then allowed to warm to ambient temperature and wasstirred for 72 hours. The reaction mixture was then diluted with waterand DCM and was filtered through a hydrophobic frit. The solvent wasremoved under reduced pressure and the remains were purified via columnchromatography to give example 9 (69.4 mg, 38%).

¹H NMR (DMSO-d₆) δ: 8.30 (s, 1H), 8.00 (d, 1H), 7.83 (d, 1H), 7.76-7.72(m, 2H), 7.70 (d, 1H), 7.58 (dd, 1H), 7.42-7.35 (m, 4H), 7.32 (t, 2H),7.26-7.21 (m, 1H), 5.31 (d, 1H), 4.01-3.92 (m, 1H), 3.15 (dd, 1H), 2.62(dd, 1H), 2.53-2.45 (m, 1H), 0.96-0.87 (m, 2H), 0.87-0.78 (m, 2H).

EXAMPLE 12:N-((2R,3S)-2-(3-CHLOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

To a stirred solution of intermediate A1 (0.25 g, 1.19 mmol, 1.0 eq) inDMF (10 mL), were added HATU (0.68 g, 1.78 mmol, 1.5 eq), DIPEA (1.0 mL,5.95 mmol, 5.0 eq) and 2,2-difluoropropanoic acid (0.17 g, 1.54 mmol,1.3 eq) and the reaction mixture was then stirred for 16 h at ambienttemperature. After completion, the reaction mixture was diluted withEtOAc and was washed with ice cold water, sat. NaHCO₃ and sat. NH₄Clsolution. The combined organic layers were concentrated to get the crudeproduct, which was purified by column chromatography (100-200 meshsilica gel; 2% MeOH-DCM; R_(f)-value-0.5) to affordN-(trans-2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.19 g, 53%).

Step 2:

A stirred solution ofN-(trans-2-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.30 g, 0.99 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.40g, 1.19 mmol, 1.2 eq) and K₃PO₄ (0.42 g, 1.98 mmol, 2.0 eq) in1,4-dioxane (20 mL) was degassed with argon for 15 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.06 g, 0.40 mmol, 0.4 eq)and CuI (0.04 g, 0.20 mmol, 0.2 eq) were added and the reaction mixturewas stirred for 16 h at 90° C. After completion, the reaction mixturewas filtered through a celite bed and the celite bed was washed 2-3times with EtOAc. The combined organic layers were concentrated to getthe crude product which was purified by column chromatography (100-200mesh silica gel; 50% EtOAc-Hexane; R_(f)-value-0.5) to afford theracemic product. Further enantiomer separation was done by preparativechiral HPLC to affordN-((2S,3R)-2-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.07 g; RT=5.32 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)andN-((2R,3S)-2-(3-chlorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)-2,2-difluoropropanamide(0.06 g, RT=7.21 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 9.48 (d, 1H), 8.32 (s, 1H), 7.89 (s, 1H), 7.77-7.71(m, 3H), 7.64 (d, 1H), 7.46 (s, 1H), 7.39 (t, 2H), 7.34-7.28 (m, 3H),5.35 (s, 1H), 4.30 (bs, 1H), 3.15-3.09 (m, 1H), 2.67-2.63 (m, 1H), 1.78(t, 3H).

EXAMPLE 13:N-TRANS-(1-(1-(4-FLUORPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(4-FLUOROPHENYL)PYRROLIDIN-3-YL)-1-METHYLCYCLOPROPANE-1-CARBOXAMIDE

N-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(4-fluorophenyl)pyrrolidin-3-yl)amine(intermediate D2, 50.0 mg, 0.124 mmol, 1.0 eq) was dissolved indichloromethan (1.4 mL) under a nitrogen atmosphere, then triethylamine(0.035 mL, 0.247 mmol, 2.0 eq) was added. The mixture was stirred forten minutes, before 1-methylcyclopropanecarbonyl chloride (0.03 mL,0.247 mmol, 2.0 eq) was added. The reaction mixture was stirred atambient temperature for 20 minutes, before sat. NaHCO₃ solution wasadded. The mixture was diluted with DCM, and was then filtered through ahydrophobic frit. The solvent was removed under reduced pressure and theremains were then purified by column chromatography and later HPLC togive example 13 (42.0 mg, 70%).

¹H NMR (DMSO-d₆) δ: 8.30 (d, 1H), 8.13 (d, 1H), 7.85 (d, 1H), 7.76-7.72(m, 2H), 7.70 (d, 1H), 7.61 (dd, 1H), 7.44-7.35 (m, 4H), 7.16-7.08 (m,2H), 5.26 (d, 1H), 4.27-4.19 (m, 1H), 3.02 (dd, 1H), 2.62 (dd, 1H), 1.31(s, 3H), 1.06-0.94 (m, 2H), 0.56 (d, 2H)

EXAMPLE 20 AND EXAMPLE 21:2,2-DIFLUORO-N-((2S,3R)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDEAND2,2-DIFLUORO-N-((2R,3S)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Step 1:

To a stirred solution of intermediate A7 (3.12 g, 13.92 mmol, 1.0 eq) inDMF (30 mL) were added HATU (7.90 g, 20.89 mmol, 1.5 eq), DIPEA (12.0mL, 69.64 mmol, 5.0 eq) and 2,2-difluoro-propionic acid (2.00 g, 18.10mmol, 1.3 eq) and the reaction mixture was stirred for 16 h at ambienttemperature. After completion, the reaction mixture was diluted withEtOAc and was washed with ice cold water, sat. NaHCO₃ and sat. NH₄Clsolution. The organic layer was concentrated to get the crude productwhich was purified by column chromatography (100-200 mesh silica gel; 2%MeOH-DCM; Re-value-0.5) to afford2,2-difluoro-N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)propanamide(3.50 g, 80%).

Step 2:

A stirred solution of2,2-difluoro-N-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)propanamide(0.30 g, 0.95 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.38g, 1.13 mmol, 1.2 eq) and K₃PO₄ (0.40 g, 1.89 mmol, 2.0 eq) in1,4-dioxane (20 mL) was degassed with argon for 15 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.05 g, 0.38 mmol, 0.4 eq)and CuI (0.04 g, 0.19 mmol, 0.2 eq) were added and the reaction mixturewas stirred for 16 h at 90° C. After completion, the reaction mixturewas filtered through a celite bed and was washed 2-3 times with EtOAc.The combined organic layers were concentrated to get the crude productwhich was purified by column chromatography (100-200 mesh silica gel;50% EtOAc-Hexane; R_(f)-value-0.5) to afford the racemic product.Further enantiomer separation was done by preparative chiral HPLC toafford2,2-difluoro-N-((2S,3R)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)propanamide(0.12 g; RT=3.08 min; Column Name: Chiralpak IA Mobile Phase: MeOH) and2,2-difluoro-N-((2R,3S)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)propanamide(0.12 g, RT=3.78 min; Column Name: Chiralpak IA Mobile Phase: MeOH) asan off white solid.

¹H NMR (DMSO-d₆) δ: 9.45-9.43 (m, 1H), 8.31 (s, 1H), 7.87-7.86 (m, 1H),7.77-7.71 (m, 3H), 7.63-7.60 (m, 1H), 7.42-7.37 (m, 2H), 7.20-7.17 (m,1H), 7.13-7.08 (m, 1H), 6.87-6.84 (m, 1H), 5.29 (s, 1H), 4.35-4.28 (m,1H), 3.78 (s, 3H), 3.13-3.07 (m, 1H), 2.67-2.61 (m, 1H), 1.83-1.78 (m,3H).

EXAMPLE 24:2,2-DIFLUORO-N-((2S,3R)-2-(2-FLUOROPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDEAND EXAMPLE 33:2,2-DIFLUORO-N-((2R,3S)-2-(2-FLUOROPHENYL-1-(1-(1-4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate A6, example 24 and example 33 weresynthesized in analogy to the synthetic procedure described for example20 and example 21.

Enantiomer separation was done by preparative chiral HPLC to affordexample 24 (0.07 g, RT=6.13 min; Column Name: Chiralpak IA (250×4.6 mm)5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min) and example 33 (0.06 g, RT=10.12 min; Column Name: Chiralpak IA(250×4.6 mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, FlowRate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 9.46-9.44 (m, 1H), 8.32 (s, 1H), 7.81 (s, 1H),7.76-7.71 (m, 3H), 7.54-7.51 (m, 1H), 7.41-7.37 (m, 3H), 7.27-7.24 (m,1H), 7.16-7.08 (m, 2H), 5.54-5.53 (m, 1H), 4.48-4.46 (m, 1H), 3.17-3.10(m, 1H), 2.70-2.64 (m, 1H), 1.81-1.71 (m, 3H).

EXAMPLE 25:2,2-DIFLUORO-N-(TRANS-1-(1-(3-FLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate B1, example 25 was synthesized in analogy tothe synthetic procedure described for example 6.

¹H NMR (DMSO-d₆) δ: 9.51-9.49 (m, 1H), 8.35 (s, 1H), 7.90 (s, 1H),7.85-7.83 (m, 1H), 7.68-7.66 (m, 1H), 7.60-7.58 (m, 3H), 7.37-7.30 (m,4H), 7.23-7.20 (m, 2H), 5.33-5.32 (m, 1H), 4.29-4.25 (m, 1H), 3.14-3.07(m, 1H), 2.65-2.60 (m, 1H), 1.83-1.74 (m, 3H).

EXAMPLE 26:N-TRANS-(1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO2-(3,5-DIFLUOROPHENYL)PYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

2,2-difluoropropanoic acid (383.9 mg, 3.488 mmol, 2.0 eq) was weighedout into a flask, a stir bar was added and the flask was sealed. Theflask was purged with nitrogen, followed by the addition of DCM (2.0 mL)and triethylamine (0.49 mL, 3.488 mmol, 2.0 eq). Propylphosphonicanhydride solution (≥50 wt. % in ethyl acetate, 2.1 mL, 3.488 mmol, 2.0eq) was added next, and the mixture was stirred for 10 minutes. Then,N-trans-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)amine (intermediate15, 370.1 mg, 1.744 mmol, 1.0 eq) was added in DCM (7 mL). The reactionmixture was stirred at ambient temperature for 16 hours. The reactionmixture was then diluted with water and EtOAc. The layers wereseparated, and the aqueous layer was extracted two more times withEtOAc. The combined organic layers were then washed with brine and driedover MgSO₄. The solvent was removed under reduced pressure and theremains were then purified via column chromatography to givetrans-2,2-difluoro-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)propanamide(466.8 mg, 88%) as a white solid.

Step 2:

Trans-2,2-difluoro-N-(5-oxo-2-(3,5-difluorophenyl)pyrrolidin-3-yl)propanamide(47.0 mg, 0.154 mmol, 1.0 eq), potassium phosphate tribasic (65.6 mg,0.309 mmol, 2.0 eq), copper iodide (5.9 mg, 0.031 mmol, 0.2 eq) and1-(4-fluorophenyl)-5-iodo-indazole (62.7 mg, 0.185 mmol, 1.2 eq) areweighed out into a vial, the vial was sealed, a stir bar was added andthe vial was purged with nitrogen. 1,4-dioxane (1.0 mL) was then added,followed by the addition of trans-cyclohexane-1,2-diamine (7.4 μL, 0.62mmol, 0.4 eq). The reaction mixture was then heated to 110° C. for 16hours. After that, the mixture was cooled to ambient temperature and wasdiluted with water and DCM. The mixture was filtered through ahydrophobic frit and the solvent was removed under reduced pressure. Theremains were purified by column chromatography and later HPLC to giveexample 26 (14.4 mg, 18%).

¹H NMR (DMSO-d₆) δ: 9.45 (d, 1H), 8.33 (d, 1H), 7.92-7.88 (m, 1H),7.79-7.72 (m, 3H), 7.64 (dd, 1H), 7.41 (t, 2H), 7.16-7.08 (m, 3H), 5.37(d, 1H), 4.42-4.28 (m, 1H), 3.14 (dd, 1H), 2.67 (dd, 1H), 1.80 (t, 3H).

EXAMPLE 27:2,2-DIFLUORO-N-(TRANS-5-OXO-2-PHENYL-1-(1-PHENYL-1H-INDAZOL-5-YL)PYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate B1, example 27 was synthesized in analogy tothe synthetic procedure described for example 6.

¹H NMR (DMSO-d₆) δ: 9.51-9.49 (m, 1H), 8.31 (s, 1H), 7.88 (s, 1H),7.78-7.70 (m, 3H), 7.65-7.63 (m, 1H), 7.58-7.54 (m, 2H), 7.40-7.23 (m,6H), 5.32 (s, 1H), 4.29-4.25 (m, 1H), 3.14-3.07 (m, 1H), 2.66-2.59 (m,1H), 1.83-1.74 (m, 3H).

EXAMPLE 28:N-((2R,3S)-2-(2-FLUOROPHENYL-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Step 1: To a stirred solution of cyclopropanecarboxylic acid (0.53 g,6.18 mmol, 1.2 eq) in DMF (8.0 mL) was added HATU (4.00 g, 10.30 mmol,2.0 eq), DIPEA (4.5 mL, 25.75 mmol, 5.0 eq) and intermediate A6 (1.00 g,5.15 mmol, 1.0 eq) at 0° C. and the reaction mixture was then stirred atambient temperature for 16 h. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reactionmixture was diluted with EtOAc (25 mL) and was washed with ice coldwater (3×25 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 2% MeOH-DCM) to affordN-(trans-2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.56 g, 41%).

Step 2:

A stirred solution ofN-(trans-2-(2-fluorophenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.250 g, 0.953 mmol, 1 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.385 g, 1.140 mmol, 1.2 eq) and K₃PO₄ (0.404 g, 1.906 mmol, 2.0 eq) in1,4-dioxane (10 mL) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.054 g, 0.381 mmol, 0.4 eq)and CuI (0.036 g, 0.191 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% methanol inDCM, Rf-0.4), the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with 1,4-dioxane. The combinedorganic layers were concentrated to get the crude product which waspurified by column chromatography (230-400 mesh silica gel; 0 to 2% MeOHin DCM) to afford the racemic product. Further enantiomer separation wasdone by preparative chiral HPLC to afford pureN-((2S,3R)-2-(2-fluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.063 g, 14%; RT=7.76 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)andN-((2R,3S)-2-(2-fluorophenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.036 g, 8%; RT=10.73 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 8.87-8.85 (m, 1H), 8.32 (s, 1H), 7.84 (s, 1H),7.76-7.71 (m, 3H), 7.57-7.55 (m, 1H), 7.42-7.37 (m, 3H), 7.27-7.26 (m,1H), 7.16-7.09 (m, 2H), 5.44 (s, 1H), 4.37-4.32 (m, 1H), 3.13-3.07 (m,1H), 2.54 (s, 1H), 1.59-1.57 (m, 1H), 0.70-0.68 (m, 4H).

EXAMPLE 29:N-(TRANS-1-(1-(4-CYANOPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

A stirred solution of intermediate B1 (0.600 g, 1.563 mmol, 1.0 eq),4-bromobenzonitrile (0.339 g, 1.875 mmol, 1.2 eq) and K₃PO₄ (0.662 g,3.125 mmol, 2.0 eq) in 1,4-dioxane (30 mL) was degassed with argon for30 min. Then, trans-N,N′-dimethylcyclohexane-1,2-diamine (0.088 g, 0.625mmol, 0.4 eq) and CuI (0.060 g, 0.3125 mmol, 0.2 eq) were added and thereaction mixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% methanol inDCM, Rf-0.4), the reaction mixture was filtered through a celite bed andthe celite bed was washed 2-3 times with 1,4-dioxane. The combinedorganic layers were concentrated to get the crude product which waspurified by column chromatography (230-400 mesh silica gel; 0 to 2% MeOHin DCM) followed by further purification using preparative HPLC toafford pureN-(trans-1-(1-(4-cyanophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(0.22 g, 29%).

¹H NMR (DMSO-d₆) δ: 9.51-9.49 (m, 1H), 8.43 (s, 1H), 8.02-7.97 (m, 4H),7.94-7.92 (m, 2H), 7.72-7.70 (m, 1H), 7.36-7.29 (m, 4H), 7.24-7.23 (m,1H), 5.34 (s, 1H), 4.27 (bs, 1H), 3.15-3.08 (m, 1H), 2.65-2.60 (m, 1H),1.83-1.73 (m, 3H).

EXAMPLE 30:N-(TRANS-1-(1-(3-CYANOPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Starting from intermediate B1, example 30 was synthesized in analogy tothe synthetic procedure described for example 29.

¹H NMR (DMSO-d₆) δ: 9.51-9.49 (m, 1H), 8.39 (s, 1H), 8.20 (s, 1H),8.11-8.09 (m, 1H), 7.92-7.89 (m, 2H), 7.84-7.82 (m, 1H), 7.77-7.75 (m,1H), 7.68-7.66 (m, 1H), 7.37-7.30 (m, 4H), 7.25-7.23 (m, 1H), 5.33 (s,1H), 4.27 (bs, 1H), 3.14-3.08 (m, 1H), 2.65-2.60 (m, 1H), 1.83-1.73 (m,3H).

EXAMPLE 34:N-((2R,3S)-2-(4-FLUORO-3-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Step 1:

To a stirred solution of intermediate A7 (0.70 g, 3.12 mmol, 1.0 eq) inDMF (30 mL) was added HATU (1.78 g, 4.68 mmol, 1.5 eq), DIPEA (2.7 mL,15.62 mmol, 5.0 eq) and cyclopropanecarboxylic acid (0.34 g, 4.06 mmol,1.3 eq) and the reaction mixture was stirred for 16 h at ambienttemperature. After completion, the reaction mixture was diluted withEtOAc and was washed with ice cold water, sat. NaHCO₃ and sat. NH₄Clsolution. The combined organic layers were concentrated under reducedpressure to get the crude product which was purified by columnchromatography (100-200 mesh silica gel; 2% MeOH-DCM; R_(f)-value-0.5)to affordN-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.70 g, 77%).

Step 2:

A stirred solution ofN-(trans-2-(4-fluoro-3-methoxyphenyl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.25 g, 0.86 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.35g, 1.02 mmol, 1.2 eq) and K₃PO₄ (0.36 g, 1.71 mmol, 2.0 eq) in1,4-dioxane (20 mL) was degassed with argon for 15 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.05 g, 0.34 mmol, 0.4 eq)and CuI (0.03 g, 0.17 mmol, 0.2 eq) were added and the reaction mixturewas stirred for 16 h at 90° C. After completion, the reaction mixturewas filtered through a celite bed and the celite bed was washed 2-3times with EtOAc. The combined organic layers were concentrated to getthe crude product which was purified by column chromatography (100-200mesh silica gel; 5% MeOH-DCM; R_(f)-value-0.5) to afford the racemicproduct. Further enantiomer separation was done by preparative chiralHPLC chiral to affordN-((2S,3R)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.07 g, RT=10.55 min; Column Name: Chiralpak ID (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EtOH/DEA: 80/20/0.1, Flow Rate: 1.0 ml/min) andN-((2R,3S)-2-(4-fluoro-3-methoxyphenyl)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.06 g, RT=13.05 min; Column Name: Chiralpak ID (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EtOH/DEA: 80/20/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 8.87 (d, 1H), 8.31 (s, 1H), 7.90-7.89 (m, 1H),7.77-7.72 (m, 3H), 7.69-7.66 (m, 1H), 7.42-7.38 (t, 2H), 7.19-7.16 (m,1H), 7.14-7.09 (m, 1H), 6.86-6.83 (m, 1H), 5.23 (s, 1H), 4.18-4.17 (m,1H), 3.79 (s, 3H), 3.11-3.05 (m, 1H), 2.44-2.43 (m, 1H), 1.61-1.58 (m,1H), 0.74-0.69 (m, 4H).

EXAMPLE 38:2,2-DIFLUORO-N-((2S,3R)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXO-2-(O-TOLYL)PYRROLIDIN-3-YL)PROPANAMIDEAND EXAMPLE 72:2,2-DIFLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(O-TOLYL)PYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate A10, example 38 and example 72 weresynthesized in analogy to the synthetic procedure described for example20 and example 21.

Enantiomer separation was done by preparative chiral HPLC to affordexample 38 (0.07 g, RT=4.01 min; Column Name: Chiralpak IA (250×4.6 mm)5 μm, Mobile Phase: Hexane/EA/EtOH/DEA:50/25/25/0.1, Flow Rate: 1.0ml/min) and example 72 (0.06 g; RT=4.99 min; Column Name: Chiralpak IA(250×4.6 mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, FlowRate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 9.63-9.61 (m, 1H), 8.32 (s, 1H), 7.87 (s, 1H),7.76-7.71 (m, 3H), 7.64-7.62 (m, 1H), 7.41-7.37 (m, 2H), 7.16-7.13 (m,4H), 5.54 (s, 1H), 4.27 (s, 1H), 3.17-3.10 (m, 1H), 2.38 (s, 3H),1.83-1.73 (m, 3H).

EXAMPLE 39:N-((2S,3R)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDEAND EXAMPLE 65:N-((2R,3S)-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL-5-OXO-2-PHENYLPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Step 1:

To a stirred solution of cyclopropanecarboxylic acid (0.59 g, 6.818mmol, 1.2 eq) in DMF (15 mL) was added HATU (4.32 g, 11.363 mmol, 2.0eq), DIPEA (5.0 mL, 28.409 mmol, 5.0 eq) and intermediate A2 (1.00 g,5.681 mmol, 1.0 eq) at 0° C. and the reaction mixture was then stirredat ambient temperature for 16 h. After completion of the reaction(monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reactionmixture was diluted with EtOAc (35 mL) and was washed with ice coldwater (3×25 mL), dried over Na₂SO₄ and concentrated under reducedpressure to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 4% MeOH-DCM) to affordN-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.45 g,32%).

Step 2:

A stirred solution ofN-(trans-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide (0.450 g,1.844 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (0.748 g,2.213 mmol, 1.2 eq) and K₃PO₄ (0.781 g, 3.688 mmol, 2.0 eq) in1,4-dioxane (30 mL) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.104 g, 0.737 mmol, 0.4 eq)and CuI (0.070 g, 0.368 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM,Rf-0.4), the reaction mixture was filtered through a celite bed and thecelite bed was washed 2-3 times with 1,4-dioxane. The combined organiclayers were concentrated to get the crude product which was purified bycolumn chromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) toafford the racemic product. Further enantiomer separation was done bypreparative chiral HPLC to afford pureN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.267 g, 32%; RT=5.56 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min) andN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropanecarboxamide(0.254 g, 30%; RT=7.13 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/Isopropanol/DCM/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min).

¹H-NMR (DMSO-d₆) δ: 8.90 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.73-7.71(d, 4H), 7.41-7.23 (m, 7H), 5.26 (s, 1H), 4.16-4.12 (m, 1H), 3.09-3.03(m, 1H), 2.42-2.32 (d, 1H), 1.62-1.58 (m, 1H), 0.71-0.69 (m, 4H).

EXAMPLE 42:2,2-DIFLUORO-N-((2S,3R)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDEAND EXAMPLE 69:2,2-DIFLUORO-N-((2R,3S)-2-(2-FLUORO-5-METHOXYPHENYL-1-(1-(4-FLUOROPHENYL-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate A11, example 42 and example 69 weresynthesized in analogy to the synthetic procedure described for example20 and example 21.

Enantiomer separation was done by preparative chiral HPLC to affordexample 42 (0.07 g, RT=7.96 min; Column Name: Chiralpak ID (250×4.6 mm)5 μm, Mobile Phase: EtOH, Flow Rate: 0.5 ml/min) and example 69 (0.06 g;RT=10.31 min; Column Name: Chiralpak ID (250×4.6 mm) 5 μm, Mobile Phase:EtOH, Flow Rate: 0.5 ml/min).

¹H NMR (DMSO-d₆): δ 9.42-9.40 (m, 1H), 8.34 (s, 1H), 7.81 (s, 1H),7.77-7.72 (m, 3H), 7.54-7.51 (m, 1H), 7.42 (t, 2H), 7.08 (t, 1H),6.92-6.90 (m, 1H), 6.80-6.77 (m, 1H), 5.51-5.50 (m, 1H), 4.49-4.48 (m,1H), 3.64 (s, 3H), 3.16-3.09 (m, 1H), 2.69-2.64 (m, 1H), 1.81-1.71 (m,3H).

EXAMPLE 43:N-((2S,3R)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDEAND EXAMPLE 62:N-((2R,3S)-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-(4-FLUORPHENYL)-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Starting from intermediate A11, example 43 and example 62 weresynthesized in analogy to the synthetic procedure described for example39 and example 65.

Enantiomer separation was done by preparative chiral HPLC to affordexample 43 (0.07 g, RT=5.05 min; Column Name: Chiralpak ID (250×4.6 mm)5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0ml/min) and example 62 (0.06 g; RT=7.12 min; Column Name: Chiralpak ID(250×4.6 mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, FlowRate: 1.0 ml/min).

¹H NMR (DMSO-d₆) δ: 8.84-8.82 (m, 1H), 8.33 (s, 1H), 7.84 (s, 1H),7.77-7.72 (m, 3H), 7.58-7.55 (m, 1H), 7.42 (t, 2H), 7.08 (t, 1H),6.87-6.85 (m, 1H), 6.80-6.77 (m, 1H), 5.42 (s, 1H), 4.37-4.35 (m, 1H),3.64 (s, 3H), 3.13-3.07 (m, 1H), 2.54-2.52 (m, 1H), 1.58-1.55 (m, 1H),0.70-0.68 (m, 4H).

EXAMPLE 49:N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-2-(2-METHOXYPYRIDIN-4-YL)-5-OXOPYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Step 1:

To a stirred solution of cyclopropanecarboxylic acid (0.50 g, 5.79 mmol,1.2 eq) in DMF (10 mL) was added HATU (3.60 g, 9.65 mmol, 2.0 eq), DIPEA(4.2 mL, 24.13 mmol, 5.0 eq) and intermediate A9 (1.00 g, 4.82 mmol, 1.0eq) at 0° C. and the reaction mixture was then stirred at ambienttemperature for 16 h. After completion of the reaction (monitored byTLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction mixture wasdiluted with EtOAc (25 mL) and was washed with ice cold water (3×25 mL),dried over Na₂SO₄ and concentrated under reduced pressure to get thecrude product which was purified by column chromatography (230-400 meshsilica gel; 0 to 2% MeOH-DCM) to affordN-(trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.88 g, 66%).

Step 2:

A stirred solution ofN-(trans-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)-cyclopropanecarboxamide(0.444 g, 1.612 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole(0.654 g, 1.935 mmol, 1.2 eq) and K₃PO₄ (0.683 g, 3.224 mmol, 2.0 eq) in1,4-dioxane (10 mL) was degassed with argon for 30 min. Thentrans-N,N′-dimethylcyclohexane-1,2-diamine (0.092 g, 0.645 mmol, 0.4 eq)and CuI (0.062 g, 0.322 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. in a sealed tube. Aftercompletion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM,Rf-0.4), the reaction mixture was filtered through a celite bed and thecelite bed was washed 2-3 times with 1,4-dioxane. The combined organiclayers were concentrated to get the crude product which was purified bycolumn chromatography (230-400 mesh silica gel; 0 to 6% MeOH in DCM) toafford the racemic product. Further enantiomer separation was done bypreparative chiral HPLC to afford pureN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.042 g; RT=8.74 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)andN-((2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-(2-methoxypyridin-4-yl)-5-oxopyrrolidin-3-yl)cyclopropanecarboxamide(0.060 g; RT=7.54 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min).

¹H NMR (DMSO-d₆): δ 8.92-8.91 (m, 1H), 8.32 (s, 1H), 8.10 (d, 1H), 7.92(s, 1H), 7.77-7.71 (m, 4H), 7.42 (t, 2H), 7.00 (d, 1H), 6.73 (s, 1H),5.25-5.24 (m, 1H), 4.18-4.14 (m, 1H), 3.77 (s, 3H), 3.11-3.04 (m, 1H),2.45-2.44 (m, 1H), 1.59 (bs, 1H), 0.76-0.70 (m, 4H).

EXAMPLE 53:N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(O-TOLYL)PYRROLIDIN-3-YL)CYCLOPROPANECARBOXAMIDE

Starting from intermediate A10, example 53 was synthesized in analogy tothe synthetic procedure described for example 28.

Enantiomer separation was done by preparative chiral HPLC to affordN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(o-tolyl)pyrrolidin-3-yl)cyclopropanecarboxamide(0.134 g, RT=4.48 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min)and example 63 (0.077 g, RT=5.32 min; Column Name: Chiralpak IA (250×4.6mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0ml/min).

¹H NMR (DMSO-d₆): δ 9.01 (d, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.76-7.72(m, 3H), 7.69-7.67 (m, 1H), 7.42-7.37 (m, 2H), 7.20-7.17 (m, 1H),7.13-7.08 (m, 3H), 5.41 (s, 1H), 4.19-4.15 (m, 1H), 3.10-3.04 (m, 1H),2.42-2.39 (m, 4H), 1.62-1.59 (m, 1H), 0.71-0.69 (m, 4H).

EXAMPLE 73:1-FLUORO-N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)CYCLOPROPANE-1-CARBOXAMIDE

Starting from intermediate A2, example 73 was synthesized in analogy tothe synthetic procedure described for example 28.

Enantiomer separation was done by preparative chiral HPLC to afford1-fluoro-N-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)cyclopropane-1-carboxamide(0.07 g; RT=7.17 min; Column Name: Chiralpak IA (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0 ml/min)and example 73 (0.10 g, RT=10.00 min; Column Name: Chiralpak IA (250×4.6mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 70/15/15/0.1, Flow Rate: 1.0ml/min).

¹H NMR (DMSO-d₆): δ 9.20-9.18 (m, 1H), 8.30 (s, 1H), 7.87 (s, 1H),7.76-7.63 (m, 4H), 7.41-7.28 (m, 6H), 7.23-7.21 (m, 1H), 5.36-5.35 (m,1H), 4.35-4.31 (m, 1H), 3.10-3.03 (m, 1H), 2.67-2.62 (m, 1H), 1.34-1.30(m, 2H), 1.21 (s, 2H).

EXAMPLE 74:N-((2R,3S)-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-1-METHYLCYCLOPROPANE-1-CARBOXAMIDE

Starting from intermediate A2, example 74 was synthesized in analogy tothe synthetic procedure described for example 28.

Enantiomer separation was done by preparative chiral HPLC to affordN-((2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-1-methylcyclopropane-1-carboxamide(0.050 g; RT=4.75 min; Column Name: Chiralpak ID (250×4.6 mm) 5 μm,Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0 ml/min)and example 74 (0.063 g, RT=6.78 min; Column Name: Chiralpak ID (250×4.6mm) 5 μm, Mobile Phase: Hexane/EA/EtOH/DEA: 50/25/25/0.1, Flow Rate: 1.0ml/min).

¹H NMR (DMSO-d₆): δ 8.30 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.73-7.66(m, 4H), 7.39-7.21 (m, 7H), 5.25 (s, 1H), 4.20 (s, 1H), 3.19-3.01 (m,1H), 2.61 (s, 1H), 1.30 (s, 3H), 1.00 (s, 2H), 0.55 (s, 2H).

EXAMPLE 75:N-(TRANS-1-(1-(4,4-DIFLUOROCYCLOHEXYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL-2,2-DIFLUOROPROPANAMIDE

A stirred solution of2,2-difluoro-N-(trans-5-oxo-2-phenylpyrrolidin-3-yl)propanamide (forsynthesis see example 2, step 1) (0.20 g, 0.75 mmol, 1.0 eq),intermediate C1 (0.32 g, 0.90 mmol, 1.2 eq) and K₃PO₄ (0.32 g, 1.49mmol, 2.0 eq) in 1,4-dioxane (20 mL) was degassed with argon for 30 min.Then, trans-N,N′-dimethylcyclohexane-1,2-diamine (0.04 g, 0.30 mmol, 0.4eq) and CuI (0.03 g, 0.15 mmol, 0.2 eq) were added and the reaction wasstirred for 16 h at 90° C. in a sealed tube. After completion of thereaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.5), thereaction mixture was filtered through a celite bed and the celite bedwas washed 2-3 times with 1,4-dioxane. The combined organic layers wereconcentrated to get the crude product which was purified by columnchromatography (230-400 mesh silica gel; 0 to 2% MeOH in DCM) to affordthe desiredN-(trans-1-(1-(4,4-difluorocyclohexyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl)-2,2-difluoropropanamide(0.06 g, 15%).

¹H NMR (DMSO-d₆): δ 9.47-9.46 (m, 1H), 8.01 (s, 1H), 7.72 (s, 1H),7.62-7.60 (m, 1H), 7.53-7.51 (m, 1H), 7.34-7.21 (m, 5H), 5.27 (s, 1H),4.79 (s, 1H), 4.26 (s, 1H), 3.11-3.05 (m, 1H), 2.63-2.58 (m, 1H),2.162.07 (m, 7H), 1.96 (s, 2H), 1.83-1.73 (m, 3H).

EXAMPLE 76:N-(TRANS-1-(1-(CYCLOHEXYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Starting from intermediate C2, example 76 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.47-9.46 (m, 1H), 7.96 (s, 1H), 7.69 (s, 1H),7.62-7.60 (m, 1H), 7.48-7.45 (m, 1H), 7.34-7.28 (m, 4H), 7.23-7.21 (m,1H), 5.25 (s, 1H), 4.51-4.47 (m, 1H), 4.27-4.23 (m, 1H), 3.10-3.04 (m,1H), 2.63-2.57 (m, 1H), 1.83-1.73 (m, 8H), 1.69-1.66 (m, 1H), 1.46-1.43(m, 2H), 1.24-1.21 (m, 1H).

EXAMPLE 77:2,2-DIFLUORO-N-(TRANS-2-(2-FLUORO-5-METHOXYPHENYL)-1-(1-METHYL-1H-INDAZOL-5-YL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Step 1:

To a stirred solution of 2,2-difluoropropanoic acid (0.35 g, 3.214 mmol,1.2 eq) in DMF (8 mL) was added HATU (2.03 g, 5.357 mmol, 2.0 eq), DIPEA(2.4 mL, 13.392 mmol, 5.0 eq) and intermediate A11 (0.60 g, 2.678 mmol,1.0 eq) at 0° C. and the reaction was stirred at ambient temperature for16 h. After completion of the reaction (monitored by TLC, TLC system 5%MeOH in DCM, Rf-0.3), the reaction mixture was diluted with EtOAc (25mL) and was washed with ice cold water (3×25 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to get the crude product which waspurified by column chromatography (230-400 mesh silica gel; 0 to 2%MeOH-DCM) to afford2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)propanamide(0.60 g, 71%).

Step 2:

A stirred solution of2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)propanamide(0.150 g, 0.474 mmol, 1.0 eq), 5-iodo-1-methyl-1H-indazole (0.146 g,0.569 mmol, 1.2 eq) and K₃PO₄ (0.200 g, 0.949 mmol, 2.0 eq) in1,4-dioxane (10 mL) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (0.027 g, 0.189 mmol, 0.4 eq)and CuI (0.018 g, 0.095 mmol, 0.2 eq) were added and the reactionmixture was stirred for 16 h at 90° C. After completion, the reactionmixture was filtered through a celite bed and the celite bed was washed2-3 times with EtOAc. The combined organic layers were concentrated toget the crude product which was purified by column chromatography(230-400 mesh silica gel; 3% MeOH-DCM; R_(f)-value-0.4) to afford2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-1-(1-methyl-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl)propanamide(0.059 g, 28%).

¹H NMR (DMSO-d₆) δ: 9.39-9.38 (m, 1H), 7.98 (s, 1H), 7.65 (s, 1H),7.56-7.54 (m, 1H), 7.40-7.37 (m, 1H), 7.05-7.01 (m, 1H), 6.88-6.87 (m,1H), 6.76-6.74 (m, 1H), 5.47 (s, 1H), 4.50-4.46 (m, 1H), 3.97 (s, 3H),3.63 (s, 3H), 3.12-3.06 (m, 1H), 2.68-2.62 (m, 1H), 1.80-1.70 (m, 3H).

EXAMPLE 78:N-(TRANS-1-(1-(2,2-DIFLUOROETHYL)-1H-INDAZOL-5-YL)-2-(2-FLUORO-5-METHOXYPHENYL-5-OXOPYRROLIDIN-3-YL-2,2-DIFLUOROPROPANAMIDE

Starting from 1-(2,2-difluoroethyl)-5-iodo-1H-indazole and2,2-difluoro-N-(trans-2-(2-fluoro-5-methoxyphenyl)-5-oxopyrrolidin-3-yl)propenamide(see example 77, step 1), example 78 was synthesized in analogy to thesynthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.41-9.39 (m, 1H), 8.11 (s, 1H), 7.69-7.63 (m, 2H),7.45-7.43 (m, 1H), 7.07-7.02 (m, 1H), 6.90 (s, 1H), 6.77 (s, 1H), 6.38(s, 1H), 5.47 (s, 1H), 4.90 (t, 2H), 4.48 (s, 1H), 3.63 (s, 3H),3.11-3.07 (m, 1H), 2.68-2.62 (m, 1H), 1.80-1.70 (m, 3H).

EXAMPLE 79:2,2-DIFLUORO-N-(TRANS-1-(1-(2-FLUOROBENZYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate C3, example 79 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.47-9.45 (m, 1H), 8.03 (s, 1H), 7.73 (s, 1H),7.63-7.61 (m, 1H), 7.50-7.47 (m, 1H), 7.32-7.21 (m, 7H), 7.12-7.08 (m,2H), 5.56 (s, 2H), 5.25 (s, 1H), 4.26-4.22 (s, 1H), 3.10-3.03 (m, 1H),2.66-2.57 (m, 1H), 1.82-1.72 (m, 3H).

EXAMPLE 80:2,2-DIFLUORO-N-(TRANS-1-(1-(3-FLUOROBENZYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate C4, example 80 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.47-9.45 (m, 1H), 8.05 (s, 1H), 7.75 (s, 1H),7.63-7.61 (m, 1H), 7.51-7.49 (m, 1H), 7.32-7.21 (m, 6H), 7.08-6.97 (m,3H), 5.60 (s, 2H), 5.26 (s, 1H), 4.27-4.23 (m, 1H), 3.10-3.03 (m, 1H),2.61-2.57 (m, 1H), 1.82-1.72 (m, 3H).

EXAMPLE 81:2,2-DIFLUORO-N-(TRANS-1-(1-(4-FLUOROBENZYL)-1H-INDAZOL-5-YL-5-OXO-2-PHENYLPYRROLIDIN-3-YL)PROPANAMIDE

Starting from intermediate C5, example 81 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.47-9.45 (m, 1H), 8.05 (s, 1H), 7.75 (s, 1H),7.64-7.61 (m, 1H), 7.51-7.48 (m, 1H), 7.32-7.27 (m, 4H), 7.23-7.21 (m,1H), 7.06-6.97 (m, 3H), 5.60 (s, 2H), 5.26 (s, 1H), 4.26-4.22 (s, 1H),3.05-3.03 (m, 1H), 2.62-2.57 (m, 1H), 1.82-1.72 (m, 3H).

EXAMPLE 82:N-(TRANS-1-(1-(CYCLOPROPYLMETHYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Starting from intermediate C6, example 82 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆) δ: 9.47-9.46 (m, 1H), 7.96 (s, 1H), 7.71 (s, 1H),7.61-7.59 (m, 1H), 7.48-7.46 (m, 1H), 7.34-7.28 (m, 4H), 7.23-7.19 (m,1H), 5.27-5.26 (m, 1H), 4.25-4.20 (m, 3H), 3.10-3.04 (m, 1H), 2.63-2.57(m, 1H), 1.83-1.73 (m, 3H), 1.21-1.19 (m, 1H), 0.46-0.42 (m, 2H),0.34-0.33 (m, 2H).

EXAMPLE 84:N-(TRANS-1-(1-((4,4-DIFLUOROCYCLOHEXYL)METHYL)-1H-INDAZOL-5-YL)-5-OXO-2-PHENYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Starting from intermediate C7, example 84 was synthesized in analogy tothe synthetic procedure described for example 75.

¹H NMR (DMSO-d₆): δ 9.48-9.46 (m, 1H), 7.99 (s, 1H), 7.70 (s, 1H),7.63-7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.33-7.22 (m, 5H), 5.26 (s, 1H),4.26-4.24 (m, 3H), 3.10-3.04 (m, 1H), 2.66-2.57 (m, 1H), 1.95-1.93 (m,3H), 1.83-1.66 (m, 5H), 1.51 (s, 2H), 1.26-1.23 (m, 2H).

EXAMPLE 85:2,2-DIFLUORO-N-((TRANS)-1-(1-(2-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOROPHENYL-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Step 1:

5-Bromo-1H-indazole (500.0 mg, 2.538 mmol, 1.0 eq) was dissolved in DMF(5 mL) and the mixture was cooled to 0° C. Then sodium hydride (60%dispersion in mineral oil, 121.8 mg, 3.045 mmol, 1.2 eq) was added, andthe mixture was stirred for 10 minutes, followed by the addition of1-(bromomethyl)-2-fluoro-benzene (0.36 mL, 3.045 mmol, 1.2 eq). Themixture was warmed to ambient temperature overnight. The reactionmixture was quenched by the addition of water. The mixture was thenextracted three times with EtOAc. The combined organic layers werewashed with water, then with brine and were then dried over MgSO₄. Thesolvent was removed and the remains were purified via columnchromatography. The desired compound was obtained in 60% yield (467.0mg).

Step 2:

5-bromo-1-(2-fluorobenzyl)-1H-indazole (64.0 mg, 0.210 mmol, 1.2 eq),copper iodide (6.7 mg, 0.035 mmol, 0.2 eq), sodium iodide (52.4 mg,0.349 mmol, 2.0 eq),2,2-difluoro-N-[(trans)-2-(4-fluorophenyl)-5-oxo-pyrrolidin-3-yl]propanamide(50.0 mg, 0.175 mmol, 1.0 eq) and K₃PO₄ (74.2 mg, 0.349 mmol, 2.0 eq)are weighed out into a vial, a stir bar was added, the vial was sealedand was purged with nitrogen. 1,4-Dioxane (1.0 mL) was added, followedby trans-N,N′-dimethylcyclohexane-1,2-diamine (9.9 mg, 0.070 mmol, 0.4eq). The mixture was heated to 110° C. for 16 hours. The mixture wascooled to ambient temperature and was then diluted with DCM and water.The mixture was filtered through a hydrophobic frit and was thenpurified via column chromatography to afford2,2-difluoro-N-((trans)-1-(1-(2-fluorobenzyl)-1H-indazol-5-yl)-2-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)propanamide(86.8 mg, 97%).

¹H NMR (DMSO-d₆) δ: 9.43 (d, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.62 (d,1H), 7.49 (dd, 1H), 7.42-7.37 (m, 2H), 7.36-7.29 (m, 1H), 7.21-7.15 (m,1H), 7.15-7.06 (m, 4H), 5.63 (s, 2H), 5.28 (d, 1H), 4.34-4.22 (m, 1H),3.07 (dd, 1H), 2.64 (dd, 1H), 1.78 (t, 3H).

EXAMPLE 86:2,2-DIFLUORO-N-((TRANS)-1-(1-(4-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOROPHENYL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Example 86 was synthesized in analogy to the synthetic proceduredescribed for example 85, substituting 1-(bromomethyl)-2-fluoro-benzenefor 1-(bromomethyl)-4-fluorobenzene in step 1 (yield 56.4%) and5-bromo-1-(2-fluorobenzyl)-1H-indazole for5-bromo-1-(4-fluorobenzyl)-1H-indazole in step 2. Example 86 wasobtained in 41% yield (36.6 mg).

¹H NMR (DMSO-d₆) δ: 9.42 (d, 1H), 8.04 (d, 1H), 7.72 (d, 1H), 7.63 (d,1H), 7.46 (dd, 1H), 7.42-7.36 (m, 2H), 7.28-7.24 (m, 2H), 7.14-7.09 (m,4H), 5.57 (s, 2H), 5.27 (d, 1H), 4.34-4.22 (m, 1H), 3.07 (dd, 1H), 2.63(dd, 1H), 1.78 (t, 3H)

EXAMPLE 87:2,2-DIFLUORO-N-((TRANS)-1-(1-(3-FLUOROBENZYL)-1H-INDAZOL-5-YL)-2-(4-FLUOROPHENYL)-5-OXOPYRROLIDIN-3-YL)PROPANAMIDE

Example 87 was synthesized in analogy to the synthetic proceduredescribed for example 85, substituting 1-(bromomethyl)-2-fluoro-benzenefor 1-(bromomethyl)-3-fluorobenzene in step 1 (yield 67%) and5-bromo-1-(2-fluorobenzyl)-1H-indazole for5-bromo-1-(3-fluorobenzyl)-1H-indazole in step 2 and requiringadditional purification of the final compound via HPLC. Example 87 wasobtained in 43% yield (38.0 mg).

¹H NMR (DMSO-d₆) δ: 9.42 (d, 1H), 8.06 (d, 1H), 7.74 (d, 1H), 7.63 (d,1H), 7.47 (dd, 1H), 7.40-7.37 (m, 2H), 7.35-7.30 (m, 1H), 7.14-7.10 (m,2H), 7.09-7.05 (m, 1H), 7.03-6.99 (m, 2H), 5.61 (s, 2H), 5.27 (d, 1H),4.33-4.23 (m, 1H), 3.07 (dd, 1H), 2.63 (dd, 1H), 1.78 (t, 3H)

EXAMPLE 89:N-(TRANS-1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-ETHYLPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

Sodium iodide (304.5 mg, 2.032 mmol, 6.0 eq.) was weighed out into amicrowave vial, a stir bar was added, the vial was sealed and spargedwith nitrogen. Thentrans-{1-[1-(4-Fluoro-phenyl)-1H-indazol-5-yl]-5-oxo-2-ethyl-pyrrolidin-3-yl}-carbamicacid benzyl ester (160.0 mg, 0.339 mmol, 1.0 eq.) in acetonitrile (8.0mL) was added, followed by the addition of TMSCl (0.17 mL, 1.354 mmol,4.0 eq.), and the resulting mixture was stirred at ambient temperaturefor 16 hours. Then ethanol (9.6 mL) was added and the resulting mixturewas purified using a cationic exchange resin to obtain 170 mg of crudeN-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-yl)amine.

Step 2:

2,2-Difluoropropanoic acid (39.0 mg, 0.355 mmol, 1.5 eq.) was weighedout into a vial, a stir bar was added, the vial was sealed and purgedwith nitrogen. Then DCM (2.3 mL) was added, followed by the addition ofT3P (≥50 wt. % in ethyl acetate, 0.28 mL, 2.0 eq.) and triethylamine(0.13 mL, 0.946 mmol, 4.0 eq.). The resulting reaction mixture wasstirred for 10 minutes at ambient temperature. ThenN-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-yl)amine(80 mg of the 170 mg obtained in step 1) in DCM (2.3 mL) was added, andthe reaction mixture was stirred at ambient temperature for 10 minutes.Then, sat. NaHCO₃ solution and more DCM was added, and the mixture wasfiltered through a hydrophobic frit. The organic layers was thenevaporated under reduced pressure and the obtained crude material waspurified via silica gel chromatography to obtain 45.0 mg ofN-(trans-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-ethylpyrrolidin-3-yl)-2,2-difluoropropanamide.

¹H NMR (DMSO-d₆) δ: 9.33 (d, 1H), 8.39 (s, 1H), 7.92 (s, 1H), 7.86-7.77(m, 3H), 7.59 (dd, 1H), 7.44 (t, 2H), 4.37-4.28 (m, 1H), 4.15 (dd, 1H),3.01 (dd, 1H), 2.52-2.44 (m, 1H), 1.80 (t, 3H), 1.66-1.54 (m, 1H),1.55-1.42 (m, 1H), 0.83 (t, 3H)

EXAMPLE 100:N-TRANS-(1-(1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL)-5-OXO-2-(5-CHLOROTHIOPHEN-2-YL)PYRROLIDIN-3-YL)CYCLOPROPANESULFONAMIDE

Step 1:

A solution of benzyl(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)carbamate (1.7 g,4.845 mmol, 1.0 eq) in TFA (15 ml) was refluxed for 16 hours. Aftercompletion of the reaction (monitored by TLC, 5% of Methanol in DCM,Rf=0.1), the TFA was evaporated under reduced pressure and the obtainedresidue was dissolved in 10% DCM in MeOH (150 ml) and was washed withsaturated aqueous NaHCO₃ (2×75 ml) and brine (50 ml). The organic layerwas then dried over Na₂SO₄ and was concentrated under reduced pressureto obtain the crude product which was purified by column chromatography(230-400 mesh silica gel; 3-5% MeOH in DCM) to affordtrans-4-amino-5-(5-chlorothiophen-2-yl)pyrrolidin-2-one (0.75 g, 71%) asa gummy liquid.

Step 2:

To a stirred solution oftrans-4-amino-5-(5-chlorothiophen-2-yl)pyrrolidin-2-one (220 mg, 1.015mmol, 1.0 eq) in DCM (15 ml), DIPEA (0.3 ml, 1.522 mmol, 1.5 eq) andcyclopropane sulfonyl chloride (214 mg, 1.522 mmol, 1.5 eq) were addedat 0° C. and the reaction was then stirred at ambient temperature for 16hours. After completion of the reaction (monitored by TLC, TLC system 5%methanol in DCM, Rf-0.3), the solvent was removed under reduced pressureto obtain a residue, which was diluted with DCM (100 mL), washed withsodium bicarbonate solution (3×50 mL), dried over Na₂SO₄ andconcentrated to obtain a residue. This residue was purified by columnchromatography (230-400 mesh silica gel; 2 to 4% MeOH-DCM) to affordN-(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)cyclopropanesulfonamide(300 mg, 92%).

Step 3:

A stirred solution ofN-(trans-2-(5-chlorothiophen-2-yl)-5-oxopyrrolidin-3-yl)cyclopropanesulfonamide(150 mg, 0.467 mmol, 1.0 eq), 1-(4-fluorophenyl)-5-iodo-1H-indazole (205mg, 0.607 mmol, 1.3 eq) and K₃PO₄ (198 mg, 0.935 mmol, 2.0 eq) in1,4-dioxane (25 ml) was degassed with argon for 30 min. Then,trans-N,N′-dimethylcyclohexane-1,2-diamine (26.6 mg, 0.187 mmol, 0.4 eq)and CuI (17.8 mg, 0.0935 mmol, 0.2 eq) were added and the reaction wasstirred for 16 hours at 90° C. in a sealed tube. After completion of thereaction (monitored by TLC, TLC system 5% methanol in DCM, Rf-0.4), thereaction mixture was concentrated under reduced pressure, diluted withethyl acetate (100 mL), washed with water (2×75 mL), dried over Na₂SO₄and concentrated under reduced pressure to get the crude product whichwas purified by HPLC to affordN-trans-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-(5-chlorothiophen-2-yl)pyrrolidin-3-yl)cyclopropanesulfonamide_(47.5mg, 17%).

¹H NMR (400 MHz, DMSO-do): 5 8.36 (s, 1H), 8.02 (d, 1H), 7.86 (bs, 1H),7.79-7.74 (m, 3H), 7.56-7.53 (m, 1H), 7.43-7.39 (m, 2H), 7.03 (d, 1H),6.93 (d, 1H), 5.48 (d, 1H), 4.07-4.05 (m, 1H), 3.20-3.14 (m, 1H),2.67-2.58 (m, 2H), 0.99-0.85 (m, 4H).

EXAMPLE 101:N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL)-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)-5-OXOPYRROLIDIN-3-YL)-22-DIFLUOROPROPANAMIDE

Step 1:

Example 101 was prepared in analogy to example 102 using5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine instead of5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine. Yield: 46%.

¹H NMR (DMSO-d₆) δ: 9.48 (d, 1H), 8.75 (d, 1H), 8.43-8.35 (m, 2H),8.24-8.15 (m, 2H), 7.42-7.36 (m, 4H), 7.32 (dd, 2H), 7.25 (d, 1H), 5.38(d, 1H), 4.38 (tt, 1H), 3.15 (dd, 1H), 2.68 (dd, 1H), 1.79 (t, 3H).

EXAMPLE 102:N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL)-1H-PYRAZOLO[3,4-C]PYRIDIN-5-YL)-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine (65.3 mg, 0.224 mmol,1.2 eq.), sodium iodide (55.9 mg, 0.373 mmol, 2.0 eq.), copper iodide(7.1 mg, 0.037 mmol, 0.2 eq.),trans-2,2-difluoro-N-(5-oxo-2-phenylpyrrolidin-3-yl)propanamide (50.0mg, 0.186 mmol, 1.0 eq.) and potassium phosphate (79.1 mg, 0.373 mmol,2.0 eq.) were weighed out into a vial, a stir bar was added, the vialwas sealed and was purged with nitrogen. 1,4-Dioxane (1.0 mL) andtrans-N,N′-dimethylcyclohexane-1,2-diamine (0.012 mL, 0.075 mmol, 0.4eq.) were then added, and the mixture was heated to 110° C. for 16hours. The mixture was cooled to ambient temperature and was dilutedwith DCM and water. The mixture was then filtered through a hydrophobicfrit and the solvent was removed. The crude compound was then purifiedvia MPLC and HPLC to yield 13.3 mg (15%) of example 102.

¹H NMR (DMSO-d₆) δ: 9.57 (d, 1H), 8.97 (d, 1H), 8.72 (d, 1H), 8.56 (d,1H), 7.89-7.79 (m, 2H), 7.42-7.36 (m, 2H), 7.33-7.29 (m, 4H), 7.22 (td,1H), 5.78 (d, 1H), 4.24 (t, 1H), 3.16 (dd, 1H), 2.69 (dd, 1H), 1.80 (t,3H).

EXAMPLE 103:N-(TRANS-2-PHENYL-1-(1-(4-FLUOROPHENYL-1H-PYRAZOLO[4,3-B]PYRIDIN-5-YL-5-OXOPYRROLIDIN-3-YL)-2,2-DIFLUOROPROPANAMIDE

Step 1:

Example 103 was prepared in analogy to example 102, using5-bromo-1-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine instead of5-bromo-1-(4-fluorophenyl)pyrazolo[3,4-c]pyridine. Yield: 61%.

¹H NMR (DMSO-d₆) δ: 9.59 (d, 1H), 8.54 (d, 1H), 8.39-8.31 (m, 2H),7.84-7.75 (m, 2H), 7.43 (dd, 2H), 7.36-7.29 (m, 4H), 7.27-7.20 (m, 1H),5.78 (d, 1H), 4.26 (ddd, 1H), 3.19 (dd, 1H), 2.68 (dd, 1H), 1.80 (t,3H).

The examples in Table 2 were synthesized in analogy to Example 1described above, using the appropriate carboxylic acid, acid chloride orsulfonyl chloride.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR 3 INT D2

35 ¹H NMR (DMSO-d₆) δ: 9.48 (d, 1H), 8.30 (d, 1H), 7.88 (d, 1H),7.76-7.72 (m, 2H), 7.71 (d, 1H), 7.64 (dd, 1H), 7.42-7.34 (m, 4H), 7.32(t, 2H), 7.26-7.22 (m, 1H), 5.32 (d, 1H), 4.34-4.25 (m, 1H), 3.11 (dd,1H), 2.64 (dd, 1H), 1.79 (t, 3H) 7 INT D3

28 ¹H NMR (DMSO-d₆) δ: 9.47 (d, 1H), 8.31 (d, 1H), 7.91-7.86 (m, 1H),7.77-7.73 (m, 2H), 7.73-7.71 (m, 1H), 7.67-7.64 (m, 1H), 7.40 (tt, 2H),7.23 (tt, 1H), 6.91 (dt, 2H), 6.82-6.79 (m, 1H), 5.30 (d, 1H), 4.33-4.26(m, 1H), 3.70 (d, 3H), 3.11 (dd, 1H), 2.64 (dd, 1H), 1.79 (t, 3H) 8 INTD2

39 ¹H NMR (DMSO-d₆) δ: 8.90 (d, 1H), 8.31 (s, 1H), 7.91 (s, 1H),7.77-7.68 (m, 4H), 7.43-7.35 (m, 4H), 7.33 (t, 2H), 7.24 (td, 1H), 5.27(d, 1H), 4.21-4.11 (m, 1H), 3.07 (ddd, 1H), 2.47 (dd, 1H), 1.65-1.57 (m,1H), 0.80-0.67 (m, 4H) 11 INT D4

78 ¹H NMR (DMSO-d₆) δ: 9.46 (d, 1H), 8.31 (s, 1H), 7.87 (d, 1H),7.77-7.72 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.45-7.36 (m, 4H), 7.14(t, 2H), 5.33 (d, 1H), 4.35-4.27 (m, 1H), 3.11 (dd, 1H), 2.66 (dd, 1H),1.79 (t, 3H) 14 INT D5

98 ¹H NMR (DMSO-d₆) δ: 9.21-9.13 (m, 1H), 8.31 (d, 1H), 7.88 (dd, 1H),7.76- 7.73 (m, 2H), 7.73-7.68 (m, 1H), 7.68- 7.56 (m, 1H), 7.42-7.37 (m,2H), 7.34 (td, 1H), 7.28-7.13 (m, 2H), 7.13-6.99 (m, 1H), 5.38 (d, 1H),4.43-4.32 (m, 1H), 3.09 (dd, 1H), 2.69 (dd, 1H), 1.37-1.30 (m, 2H),1.30-1.13 (m, 2H) 15 INT D5

50 ¹H NMR (DMSO-d₆) δ: 8.50 (d, 1H), 8.30 (d, 1H), 7.86 (d, 1H),7.76-7.69 (m, 3H), 7.61 (dd, 1H), 7.41-7.37 (m, 2H), 7.36- 7.28 (m, 1H),7.23-7.14 (m, 2H), 7.08- 6.99 (m, 1H), 5.27 (d, 1H), 4.38-4.19 (m, 1H),3.06 (dd, 1H), 2.63-2.55 (m, 1H), 1.42-1.31 (m, 2H), 1.32-1.22 (m, 2H)17 INT D3

57 ¹H NMR (DMSO-d₆) δ: 8.48 (d, 1H), 8.31 (s, 1H), 7.88 (s, 1H),7.78-7.73 (m, 2H), 7.72 (d, 1H), 7.64 (d, 1H), 7.40 (t, 2H), 7.23 (t,1H), 6.92-6.87 (m, 2H), 6.79 (d, 1H), 5.23 (d, 1H), 4.30-4.21 (m, 1H),3.70 (s, 3H), 3.05 (dd, 1H), 2.56 (dd, 1H), 1.49-1.36 (m, 2H), 1.34-1.19(m, 2H) 19 INT D5

100 ¹H NMR (DMSO-d₆) δ: 8.45 (d, 1H), 8.31 (d, 1H), 7.91 (d, 1H),7.79-7.64 (m, 4H), 7.43-7.33 (m, 3H), 7.21 (dd, 2H), 7.10- 7.03 (m, 1H),5.27 (d, 1H), 4.20-4.13 (m, 1H), 3.12-3.02 (m, 2H), 2.47 (dd, 1H),2.22-2.11 (m, 2H), 2.07-2.02 (m, 2H), 1.95-1.87 (m, 1H), 1.83-1.75 (m,1H) 23 INT D3

100 ¹H NMR (DMSO-d₆) δ: 9.15 (d, 1H), 8.25 (s, 1H), 7.86 (d, 1H),7.73-7.69 (m, 2H), 7.68-7.61 (m, 2H), 7.34 (t, 2H), 7.19 (t, 1H),6.94-6.88 (m, 2H), 6.76 (dd, 1H), 5.33 (d, 1H), 4.41-4.33 (m, 1H), 3.06(dd, 1H), 2.66 (dd, 1H), 1.33-1.26 (m, 2H), 1.23-1.17 (m, 2H) 31 INT D6

42 ¹H NMR (DMSO-d₆) δ: 8.32 (d, 1H), 7.93- 7.86 (m, 1H), 7.80-7.69 (m,3H), 7.66- 7.63 (m, 1H), 7.47-7.46 (m, 1H), 7.40 (t, 2H), 7.37-7.27 (m,4H), 5.35 (d, 1H), 4.36-4.28 (m, 1H), 3.13 (dd, 1H), 2.67 (dd, 1H), 1.80(t, 3H) 32 INT D6

69 ¹H NMR (DMSO-d₆) δ: 8.45 (d, 1H), 8.31 (d, 1H), 7.91 (d, 1H),7.78-7.70 (m, 3H), 7.67 (dd, 1H), 7.46 (d, 1H), 7.45-7.35 (m, 2H), 7.34(d, 1H), 7.33-7.27 (m, 2H), 5.26 (d, 1H), 4.18-4.14 (m, 1H), 3.11- 3.02(m, 2H), 2.48 (dd, 1H), 2.23-2.11 (m, 2H), 2.11-2.02 (m, 2H), 1.96-1.87(m, 1H), 1.83-1.74 (m, 1H) 36 INT D7

74 ¹H NMR (DMSO-d₆) δ: 9.19 (d, 1H), 8.38 (d, 1H), 7.86 (d, 1H),7.84-7.75 (m, 3H), 7.49 (dd, 1H), 7.44 (t, 2H), 4.82 (p, 1H), 3.63 (dd,1H), 2.84-2.70 (m, 2H), 1.80 (t, 3H), 0.92-0.80 (m, 1H), 0.38-0.24 (m,1H), 0.22-0.15 (m, 1H), 0.02-−0.07 (m, 1H), −0.24 (dt, 1H) 45 INT D4

84 ¹H NMR (DMSO-d₆) δ: 8.94 (dd, 1H), 8.30 (dd, 1H), 7.88 (dd, 1H),7.76-7.72 (m, 2H), 7.72-7.70 (m, 1H), 7.63 (ddd, 1H), 7.43-7.37 (m, 4H),7.14 (td, 2H), 5.26 (dd, 1H), 4.98-4.70 (m, 1H), 4.22- 4.16 (m, 1H),3.18-3.00 (m, 1H), 2.61- 2.41 (m, 1H), 1.98-1.70 (m, 1H), 1.62- 1.54 (m,1H), 1.11-0.99 (m, 1H)

46 INT D3

38 ¹H NMR (DMSO-d₆) δ: 9.08 (d, 1H), 8.31 (d, 1H), 7.94-7.89 (m, 1H),7.79-7.67 (m, 4H), 7.44-7.36 (m, 2H), 7.24 (t, 1H), 6.94-6.88 (m, 2H),6.83-6.76 (m, 1H), 5.24 (d, 1H), 4.92-4.73 (m, 1H), 4.21- 4.11 (m, 1H),3.70 (s, 3H), 3.09 (dd, 1H), 2.48 (dd, 1H), 2.17-2.10 (m, 1H), 1.47-1.37 (m, 1H), 1.22-1.15 (m, 1H) 48 INT D7

61 ¹H NMR (DMSO-d₆) δ: 9.26 (d, 1H), 8.40 (d, 1H), 7.88 (dd, 1H),7.88-7.78 (m, 3H), 7.50 (dd, 1H), 7.45 (t, 2H), 4.43- 4.14 (m, 1H), 3.46(dd, 1H), 3.03 (dd, 1H), 2.47 (dd, 1H), 1.80 (t, 3H), 1.11-0.94 (m, 1H),0.40-0.34 (m, 1H), 0.31-0.18 (m, 2H), −0.01-−0.09 (m, 1H) 52 INT D5

80 ¹H NMR (DMSO-d₆) δ: 8.82 (t, 1H), 8.31 (d, 1H), 7.93 (d, 1H),7.80-7.65 (m, 4H), 7.43-7.31 (m, 3H), 7.25-7.17 (m, 2H), 7.11-7.03 (m,1H), 5.39-5.17 (m, 1H), 4.28-4.01 (m, 1H), 3.10 (dd, 1H), 2.49- 2.43 (m,1H), 1.38-1.31 (m, 1H), 1.26- 1.11 (m, 1H), 1.09-1.03 (m, 3H), 0.99-0.90 (m, 1H), 0.60-0.52 (m, 1H) 54 INT D4

71 ¹H NMR (DMSO-d₆) δ: 8.88 (d, 1H), 8.31 (s, 1H), 7.90 (d, 1H),7.79-7.69 (m, 3H), 7.67 (dd, 1H), 7.44-7.36 (m, 4H), 7.14 (t, 2H), 5.27(d, 1H), 4.20-4.13 (m, 1H), 3.08 (dd, 1H), 2.51-2.44 (m, 1H), 1.65- 1.57(m, 1H), 0.79-0.68 (m, 4H) 55 INT D3

84 ¹H NMR (DMSO-d₆) δ: 8.88 (d, 1H), 8.31 (s, 1H), 7.95-7.89 (m, 1H),7.78-7.69 (m, 4H), 7.44-7.36 (m, 2H), 7.29-7.20 (m, 1H), 6.94-6.89 (m,2H), 6.82-6.80 (m, 1H), 5.24 (d, 1H), 4.19-4.13 (m, 1H), 3.70 (d, 3H),3.07 (dd, 1H), 2.46 (dd, 1H), 1.67-1.57 (m, 1H), 0.80-0.68 (m, 4H) 56INT D4

89 ¹H NMR (DMSO-d₆) δ: 8.94 (dd, 1H), 8.31 (dd, 1H), 7.87 (dd, 1H),7.76-7.70 (m, 3H), 7.63 (ddd, 1H), 7.46-7.30 (m, 4H), 7.14 (td, 2H),5.26 (dd, 1H), 4.84 (dtd, 1H), 4.22-4.16 (m, 1H), 3.12-3.06 (m, 1H),2.48 (t, 1H), 1.87-1.80 (m, 1H), 1.62-1.53 (m, 1H), 1.10-1.04 (m, 1H)

61 INT D5

72 ¹H NMR (DMSO-d₆) δ: 8.90 (d, 1H), 8.30 (s, 1H), 7.91 (d, 1H),7.78-7.65 (m, 4H), 7.43-7.29 (m, 3H), 7.25-7.17 (m, 2H), 7.09-7.02 (m,1H), 5.29 (d, 1H), 4.22- 4.16 (m, 1H), 3.10 (dd, 1H), 2.53-2.46 (m, 1H),1.66-1.56 (m, 1H), 0.80-0.66 (m, 4H) 63 INT D3

53 ¹H NMR (DMSO-d₆) δ: 8.94 (dd, 1H), 8.32 (dd, 1H), 7.91 (dd, 1H),7.77-7.63 (m, 4H), 7.43-7.38 (m, 2H), 7.24 (t, 1H), 6.93-6.87 (m, 2H),6.81 (ddd, 1H), 5.24 (dd, 1H), 4.93-4.74 (m, 1H), 4.25-4.10 (m, 1H),3.70 (s, 3H), 3.11-3.05 (m, 1H), 2.47 (dt, 1H), 1.87-1.80 (m, 1H), 1.63-1.54 (m, 1H), 1.11-1.03 (m, 1H)

67 INT D6

59 ¹H NMR (DMSO-d₆) δ: 8.90 (d, 1H), 8.32 (d, 1H), 7.92 (d, 1H),7.79-7.71 (m, 3H), 7.72-7.67 (m, 1H), 7.45 (d, 1H), 7.44- 7.36 (m, 2H),7.38-7.32 (m, 1H), 7.33- 7.28 (m, 2H), 5.28 (d, 1H), 4.21-4.14 (m, 1H),3.10 (dd, 1H), 2.51-2.45 (m, 1H), 1.65-1.57 (m, 1H), 0.80-0.69 (m, 4H)68 INT D5

93 ¹H NMR (DMSO-d₆) δ: 9.48 (d, 1H), 8.30 (d, 1H), 7.88 (d, 1H),7.78-7.66 (m, 3H), 7.62 (dd, 1H), 7.44-7.27 (m, 3H), 7.26- 7.16 (m, 2H),7.05 (td, 1H), 5.35 (d, 1H), 4.38-4.29 (m, 1H), 3.12 (dd, 1H), 2.66(ddd, 1H), 1.78 (t, 3H) 70 INT D4

82 ¹H NMR (DMSO-d₆) δ: 9.15 (d, 1H), 8.31 (s, 1H), 7.86 (d, 1H),7.77-7.73 (m, 2H), 7.71 (d, 1H), 7.62 (dd, 1H), 7.45-7.37 (m, 4H),7.16-7.09 (m, 2H), 5.37 (d, 1H), 4.41-4.30 (m, 1H), 3.07 (dd, 1H), 2.69(dd, 1H), 1.39-1.24 (m, 2H), 1.26-1.14 (m, 2H) 71 INT D4

44 ¹H NMR (DMSO-d₆) δ: 8.47 (d, 1H), 8.31 (d, 1H), 7.86 (d, 1H),7.77-7.73 (m, 2H), 7.71 (d, 1H), 7.61 (dd, 1H), 7.43-7.36 (m, 4H), 7.13(td, 2H), 5.25 (d, 1H), 4.30- 4.22 (m, 1H), 3.05 (dd, 1H), 2.58 (dd,1H), 1.40 (d, 2H), 1.30-1.22 (m, 2H) 88 INT D8

46 ¹H NMR (600 MHz, DMSO-d₆) δ 9.22 (d, 1H), 8.43 (d, 1H), 8.11-8.04 (m,1H), 7.91-7.78 (m, 3H), 7.78-7.70 (m, 1H), 7.50-7.40 (m, 2H), 7.31-7.22(m, 2H), 7.25-7.17 (m, 1H), 7.17-7.11 (m, 2H), 4.67-4.59 (m, 1H),4.35-4.26 (m, 1H), 2.95-2.81 (m, 2H), 2.63-2.54 (m, 1H), 2.34-2.24 (m,1H), 1.69 (t, J = 19.5 Hz, 3H). 90 INT D9

46 ¹H NMR (DMSO-d₆) δ: 9.25 (d, 1H), 8.38 (d, 1H), 7.90 (dd, 1H),7.84-7.77 (m, 3H), 7.56 (dd, 1H), 7.46-7.40 (m, 2H), 4.90-4.76 (m, 1H),4.58 (ddd, 1H), 2.82 (dd, 1H), 2.66 (dd, 1H), 1.80 (t, 3H), 1.53 (ddd,1H), 1.09 (ddd, 1H), 0.48 (dtt, 1H), 0.36-0.18 (m, 2H), −0.09-−0.20 (m,2H). 91 INT D2- ent1

86 ¹H NMR (DMSO-d₆) δ: 8.56 (d, 1H), 8.30 (s, 1H), 7.89 (d, 1H),7.76-7.69 (m, 3H), 7.64 (dd, 1H), 7.43-7.28 (m, 6H), 7.27- 7.20 (m, 1H),5.26 (d, 1H), 4.16 (tt, 1H), 3.06 (dd, 1H), 2.46 (dd, 1H), 2.12-2.03 (m,3H), 1.00 (tt, 1H), 0.45 (ddt, 2H), 0.15 (dt, 2H). 92 INT D2- ent2

67 ¹H NMR (DMSO-d₆) δ: 8.89 (d, 1H), 8.29 (d, 1H), 7.86 (dd, 1H), 7.78(d, 1H), 7.76- 7.72 (m, 2H), 7.69 (dt, 1H), 7.62 (dd, 1H), 7.43-7.35 (m,4H), 7.30 (t, 2H), 7.25- 7.18 (m, 1H), 6.64 (d, 1H), 5.42 (d, 1H), 4.47(ddt, 1H), 3.93 (s, 3H), 3.06 (dd, 1H), 2.73 (dd, 1H). 93 INT D2- ent2

24 ¹H NMR (DMSO-d₆) δ: 9.21 (d, 1H), 8.29 (d, 1H), 7.84 (d, 1H),7.76-7.71 (m, 2H), 7.69 (d, 1H), 7.60 (dd, 1H), 7.43-7.36 (m, 4H),7.31-7.27 (m, 3H), 7.23-7.18 (m, 1H), 7.09 (s, 1H), 5.45 (d, 1H), 4.50(tt, 1H), 3.07 (dd, 1H), 2.77 (dd, 1H). 94 INT D2- ent2

27 ¹H NMR (600 MHz, DMSO-d₆) δ 9.27 (d, 1H), 8.30 (s, 1H), 7.92 (d, 1H),7.78-7.66 (m, 5H), 7.44-7.37 (m, 4H), 7.36-7.30 (m, 2H), 7.27-7.21 (m,1H), 5.40 (d, 1H), 4.43-4.36 (m, 1H), 3.15 (dd, 1H), 2.65 (dd, 1H), 2.50(s, 3H). 95 INT D2- ent2

54 ¹H NMR (DMSO-d₆) δ: 9.07 (s, 1H), 9.03 (d, 1H), 8.30 (s, 1H), 7.91(s, 1H), 7.78- 7.64 (m, 4H), 7.44-7.37 (m, 4H), 7.34 (t, 2H), 7.24 (t,1H), 5.41 (d, 1H), 4.40 (dt, 1H), 3.13 (dd, 1H), 2.66 (dd, 1H), 2.62 (s,3H). 96 INT D2- ent2

53 ¹H NMR (600 MHz, DMSO-d₆) δ 9.68 (d, 1H), 8.99 (d, 1H), 8.29 (d, 1H),7.88 (d, 1H), 7.77-7.67 (m, 4H), 7.66-7.61 (m, 1H), 7.43-7.35 (m, 4H),7.31 (t, 2H), 7.25- 7.19 (m, 1H), 5.50 (d, 1H), 4.54 (tt, 4.6 Hz, 1H),3.17-3.10 (m, 1H), 2.82-2.75 (m, 1H). 97 INT D2- ent2

44 ¹H NMR (DMSO-d₆) δ: 9.39 (d, 1H), 9.10 (dd, 1H), 8.74 (dd, 1H),8.32-8.25 (m, 2H), 7.94 (t, 1H), 7.77-7.70 (m, 4H), 7.55 (ddd, 1H),7.46-7.32 (m, 6H), 7.26 (td, 1H), 5.46 (d, 1H), 4.44 (ddd, 1H), 3.19(dd, 1H), 2.69 (dd, 1H). 98 INT D2- ent2

75 ¹H NMR (DMSO-d₆) δ: 8.73 (d, 1H), 8.30 (d, 1H), 7.92 (d, 1H),7.76-7.73 (m, 2H), 7.71 (d, 1H), 7.68 (dd, 1H), 7.42-7.37 (m, 4H), 7.34(t, 2H), 7.27-7.22 (m, 1H), 5.29 (d, 1H), 4.75-4.60 (m, 4H), 4.19 (tt,1H), 3.89-3.74 (m, 1H), 3.12-3.06 (m, 1H), 2.45 (dd, 1H).

The examples in Table 3 were synthesized in analogy to the Example 9described above, using the appropriate carboxylic acid, acid chloride orsulfonyl chloride.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR 10 INT D3

42 ¹H NMR (DMSO-d₆) δ: 8.32 (s, 1H), 7.99 (d, 1H), 7.85 (s, 1H),7.77-7.73 (m, 2H), 7.72 (d, 1H), 7.60 (dd, 1H), 7.40 (t, 2H), 7.24 (t,1H), 6.95-6.90 (m, 2H), 6.84- 6.79 (m, 1H), 5.29 (d, 1H), 4.00-3.93 (m,1H), 3.70 (s, 3H), 3.15 (dd, 1H), 2.60 (dd, 1H), 2.53-2.47 (m, 1H),0.98-0.88 (m, 2H), 0.88-0.81 (m, 2H) 37 INT D6

55 ¹H NMR (DMSO-d₆) δ: 8.32 (s, 1H), 8.01 (d, 1H), 7.87 (d, 1H),7.79-7.70 (m, 3H), 7.61 (dd, 1H), 7.47-7.43 (m, 1H), 7.44- 7.28 (m, 5H),5.34 (d, 1H), 4.02-3.97 (m, 1H), 3.13 (dd, 1H), 2.91 (d, 2H), 2.59 (dd,1H), 0.98-0.89 (m, 1H), 0.57-0.48 (m, 2H), 0.31-0.23 (m, 2H) 51 INT D4

80 ¹H NMR (DMSO-d₆) δ: 8.31 (s, 1H), 7.98 (d, 1H), 7.82 (s, 1H),7.78-7.67 (m, 3H), 7.55 (dd, 1H), 7.46-7.36 (m, 4H), 7.14 (t, 2H), 5.30(d, 1H), 4.01-3.93 (m, 1H), 3.15 (dd, 1H), 2.63 (dd, 1H), 2.51-2.45 (m,1H), 0.98-0.88 (m, 2H), 0.88-0.79 (m, 2H) 99 INT D2- ent2

35 ¹H NMR (DMSO-d₆) δ: 9.35 (t, 1H), 8.30 (t, 1H), 8.26 (d, 1H), 7.79(dd, 1H), 7.76- 7.66 (m, 3H), 7.53 (dt, 1H), 7.43-7.35 (m, 2H),7.30-7.18 (m, 6H), 5.27 (d, 1H), 3.90-3.84 (m, 1H), 2.99 (dd, 1H), 2.45-2.38 (m, 1H)

The examples in Table 4 were synthesized in analogy to the Example 13described above, using the appropriate carboxylic acid, acid chloride orsulfonyl chloride.

Inter- Ex. mediate Yield # (INT) Structure (%) ¹H NMR 16 INT D5

21 ¹H NMR (DMSO-d₆) δ: 8.31 (d, 1H), 7.85 (d, 1H), 7.78-7.66 (m, 3H),7.58 (dd, 1H), 7.43-7.29 (m, 3H), 7.24-7.18 (m, 2H), 7.10-7.01 (m, 1H),5.32 (d, 1H), 4.02-3.96 (m, 1H), 3.14 (dd, 1H), 2.87 (s, 3H), 2.58 (dd,1H) 18 INT D5

100 ¹H NMR (DMSO-d₆) δ: 8.31 (d, 1H), 8.19- 8.13 (m, 1H), 7.89 (t, 1H),7.79-7.63 (m, 4H), 7.44-7.31 (m, 3H), 7.25-7.16 (m, 2H), 7.09-7.01 (m,1H), 5.31-5.26 (m, 1H), 4.28-4.20 (m, 1H), 3.05 (ddd, 1H), 2.67-2.59 (m,1H), 1.32 (d, 3H), 1.07-0.96 (m, 2H), 0.59-0.54 (m, 2H) 22 INT D3

23 ¹H NMR (DMSO-d₆) δ: 8.31 (d, 1H), 8.13 (d, 1H), 7.88 (d, 1H),7.77-7.74 (m, 2H), 7.72 (d, 1H), 7.66 (dd, 1H), 7.44-7.37 (m, 2H), 7.22(t, 1H), 6.93-6.87 (m, 2H), 6.79 (ddd, 1H), 5.24 (d, 1H), 4.24-4.19 (m,1H), 3.70 (s, 3H), 3.01 (dd, 1H), 2.59 (dd, 1H), 1.31 (s, 3H), 1.04-0.97(m, 2H), 0.60-0.54 (m, 2H) 66 INT D5

39 ¹H NMR (DMSO-d₆) δ: 8.69 (d, 1H), 8.30 (d, 1H), 7.91 (d, 1H),7.79-7.68 (m, 3H), 7.66 (dd, 1H), 7.43-7.29 (m, 3H), 7.25- 7.16 (m, 2H),7.09-7.02 (m, 1H), 5.29 (d, 1H), 4.20-4.13 (m, 1H), 3.09 (dd, 1H), 2.45(dd, 1H), 1.90 (s, 3H)

GRE Agonist

The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary(CHO) cell line (Leibniz Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures GmbH: ACC-110) containing a fireflyluciferase gene under the control of the GR ligand binding domain fusedto the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integratedinto CHO cells. This cell line was established by stable transfection ofCHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequentstep the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.This fusion construct activated firefly luciferase expression under thecontrol of a multimerized GAL4 upstream activation sequence (UAS). Thesignal of the emitted luminescence was recorded by the FLIPR^(TERTA).This allowed for specific detection of ligand-induced activation of theGR and therefore for the identification of compounds with agonisticproperties. The GAL4/UAS reporter was premixed with a vector thatconstitutively expressed Renilla luciferase, which served as an internalpositive control for transfection efficiency.

The complete culture medium for the assay was:

-   -   DMEM F-12 (1:1) MIXTURE (LONZA cat. No: BE04-687F/U1) 500 mL    -   5 mL of 100 mM Sodium Pyruvate (LONZA cat. No: BE12-115E)    -   25 mL of 7.5% Sodium Bicarbonate (LONZA cat. No BE17-613E)    -   6.5 mL of 1 M Hepes (LONZA cat. No: BE17-737E)    -   5 mL of 100× Penicillin/Streptomycin (LONZA cat. No DE17-602E)    -   50 mL of Fetal Bovine Serum (Euroclone cat. No ECS 0180L)    -   0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1)    -   0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)

Cryo-preserved CHO-Gal4/GR cells were suspended in complete medium and5000 cells/25 μl/well were seeded into the wells of 384-well polystyreneassay plates (Thermo Scientific, cat. #4332) and cultured at 37° C., 5%CO₂ and 95% humidity. After 24 hours growth medium was carefully removedand replaced by 30 μl Opti-MEM (GIBCO, cat. #31985062) as assay buffer.To test the compounds an 8-point half-log compound dilution curve wasgenerated in 100% DMSO starting from a 2 mM stock and compounds werethen diluted 1:50 in Opti-MEM. 10 μl of compounds were then added to thewells containing 30 μl Opti-MEM resulting in a final assay concentrationrange from 10 μM to 0.003 M in 0.5% DMSO. Compounds were tested at 8concentrations in quadruplicate data points. Cells were incubated for 6hour with compounds and beclometasone (Sigma, cat. # Y0000351) ascontrol compound at 37° C., 5% CO₂ and 95% humidity in a total volume of40 μl. Finally, cells were lysed with 20 μl of Triton/Luciferin solutionand the signal of the emitted luminescence was recorded at theFLIPR^(TERTA) for 2 minutes.

The relative efficacy of a compound (% effect) was calculated based onthe full effect of the agonist beclometasone:

% effect=((compound−min)/(max−min))×100

[min=Opti-MEM only, max=beclometasone]

To calculate EC50, max, min and slope factor for each compound aconcentration response curve was fitted by plotting % effect versuscompound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((10C)/x)D)

[A=min y, B=max y, C=log EC₅₀ , D=slope]

GRE Antagonist

The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary(CHO) cell line (Leibniz Institute DSMZ—German Collection ofMicroorganisms and Cell Cultures GmbH: ACC-110) containing a fireflyluciferase gene under the control of the GR ligand binding domain fusedto the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integratedinto CHO cells. This cell line was established by stable transfection ofCHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequentstep the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4containing the DNA binding domain of GAL4 from pFA-AT2 was transfected.This fusion construct activated firefly luciferase expression under thecontrol of a multimerized GAL4 upstream activation sequence (UAS). Thesignal of the emitted luminescence was recorded by the FLIPR^(TERTA).This allowed for specific detection of antagonistic properties ofcompounds by measuring the ligand-induced inhibition ofbeclometasone-activated GR. The GAL4/UAS reporter was premixed with avector that constitutively expressed Renilla luciferase, which served asan internal positive control for transfection efficiency.

The complete culture medium for the assay was:

DMEM F-12 (1:1) MIXTURE (LONZA cat. No: BE04-687F/U1) 500 mL

5 mL of 100 mM Sodium Pyruvate (LONZA cat. No: BE12-115E)

25 mL of 7.5% Sodium Bicarbonate (LONZA cat. No BE17-613E)

6.5 mL of 1 M Hepes (LONZA cat. No: BE17-737E)

5 mL of 100× Penicillin/Streptomycin (LONZA cat. No DE17-602E)

50 mL of Fetal Bovine Serum (Euroclone cat. No ECS 0180L)

0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1)

0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)

Cryo-preserved CHO-Gal4/GR cells were suspended in complete medium and5000 cells/25 μl/well were seeded into the wells of 384-well polystyreneassay plates (Thermo Scientific, cat. #4332) and cultured at 37° C., 5%CO₂ and 95% humidity. After 24 hours growth medium was carefully removedand replaced by 20 μl Opti-MEM (GIBCO, cat. #31985062) as assay buffer.For testing compounds an 8-point half-log compound dilution curve wasgenerated in 100% DMSO starting from a 2 mM stock and compounds werethen diluted 1:50 in Opti-MEM. To test the compounds in the antagonistmode 10 μl of compounds were then added to the wells containing 20 μlOpti-MEM and incubated for 10 min. After this pre-incubation 10 μl ofthe reference agonist beclometasone (Sigma, cat. # Y0000351) at an EC50of 2.5 nM were added resulting in a final assay concentration range from10 μM to 0.003 μM in 0.5% DMSO in a total volume of 40 μl. Compoundswere tested at 8 concentrations in quadruplicate data points. Cells wereincubated for 6 hour with compounds and mifepristone as control compound(Sigma, cat. # M8046) at 37° C., 5% CO₂ and 95% humidity. Finally, cellswere lysed with 20 μl of Triton/Luciferin solution and the signal of theemitted luminescence was recorded at the FLIPR^(TETRA) for 2 minutes.

The relative efficacy of a compound (% effect) was calculated based onthe full effect of the antagonist mifepristone:

% effect=((compound−min)/(max−min))×−100

[min=Opti-MEM only, max=mifepristone]

To calculate IC₅₀, max, min and slope factor for each compound aconcentration response curve was fitted by plotting % effect versuscompound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((10C)/x)D)

[A=min y, B=max y, C=log IC₅₀ , D=slope]

TABLE 5 IC50 or EC50 A < 100 nM, B = 100 nM-1 μM, Cpd # C = 1 μM-15 μM 1 A  2 A  4 A  5 A  7 A  8 A  9 B  10 B  12 A  13 A  14 A  15 A  16 A 17 A  18 A  19 A  20 B  21 A  22 A  24 B  25 B  26 A  27 A  28 A  29 B 30 B  31 A  32 A  34 A  36 B  37 B  38 B  39 B  42 C  43 C  44 C  45 A 46 A  47 B  48 B  49 B  51 A  52 A  53 A  54 A  55 A  56 A  61 A  62 A 63 A  65 A  66 A  67 A  75 B  76 B  77 C  78 C  79 A  80 A  81 A  82 B 85 B  86 A  87 B  88 A  89 A  90 C  91 C  92 A  93 A  94 A  95 A  96 B 97 B  98 B  99 A 100 B 101 A 102 B 103 B

1. A compound according to general formula (I),

wherein R₁ represents —C₁₋₁₀-alkyl; —C₃₋₁₀cycloalkyl;—C₁₋₆-alkylene-C₃₋₁₀cycloalkyl; 3 to 7 membered heterocycloalkyl;—C₁₋₆-alkylene-(3 to 7 membered heterocycloalkyl); aryl;—C₁₋₆-alkylene-aryl; 5 or 6-membered heteroaryl; or —C₁₋₆-alkylene-(5 or6-membered heteroaryl); R₂ represents —C(═O)—C₁₋₁₀-alkyl;—C(═O)—C₃₋₁₀-cycloalkyl; —C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—C(═O)-(3 to 7 membered heterocycloalkyl); —C(═O)—C₁₋₆-alkylene-(3 to 7membered heterocycloalkyl); —C(═O)-aryl; —C(═O)—C₁₋₆-alkylene-aryl;—C(═O)-(5 or 6-membered heteroaryl); —C(═O)—C₁₋₆-alkylene-(5 or6-membered heteroaryl); —S(═O)₁₋₂—C₁₋₁₀-alkyl;—S(═O)₁₋₂—C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂-(3 to 7 membered heterocycloalkyl); —S(═O)₁₋₂—C₁₋₆-alkylene-(3to 7 membered heterocycloalkyl); —S(═O)₁₋₂-aryl;—S(═O)₁₋₂—C₁₋₆-alkylene-aryl; —S(═O)₁₋₂-(5 or 6-membered heteroaryl); or—S(═O)₁₋₂—C₁₋₆-alkylene-(5 or 6-membered heteroaryl); R₃ represents—C₁₋₁₀-alkyl; —C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl;—C₁₋₆-alkylene-aryl; —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-aryl;—C(═O)—C₁₋₆-alkylene-aryl; —S(═O)₁₋₂—C₁₋₁₀-alkyl;—S(═O)₁₋₂—C₃₋₁₀-cycloalkyl; —S(═O)₁₋₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl;—S(═O)₁₋₂-aryl; or —S(═O)₁₋₂—C₁₋₆-alkylene-aryl; R₄ represents —H; —F;—Cl; —Br; —I; —CN; —CH₃; —CF₃; —CF₂H; —CFH₂ or cyclopropyl; X representsN or CR₅; wherein R₅ represents —H; —F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkylor —C₃₋₁₀-cycloalkyl; Y represents N or CR₆; wherein R₆ represents —H;—F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkyl or —C₃₋₁₀-cycloalkyl; Z represents Nor CR₇; wherein R₇ represents —H; —F; —Cl; —Br; —I; —CN; —C₁₋₁₀-alkyl or—C₃₋₁₀-cycloalkyl; wherein —C₁₋₁₀-alkyl, —C₁₋₄-alkyl and —C₁₋₆-alkylene-in each case independently from one another is linear or branched,saturated or unsaturated; wherein —C₁₋₁₀-alkyl, —C₁₋₄-alkyl,—C₁₋₆-alkylene-, —C₃₋₁₀-cycloalkyl and 3 to 7 membered heterocycloalkylin each case independently from one another are unsubstituted or mono-or polysubstituted with one or more substituents selected from —F; —Cl;—Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH₂;—C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O; —OCF₃; —OCF₂H;—OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl; —O—C(═O)—C₁₋₆-alkyl;—O—C(═O)—O—C₁₋₆-alkyl; —O—(CO)—NH(C₁₋₆-alkyl); —O—C(═O)—N(C₁₋₆-alkyl)₂;—O—S(═O)₂—NH₂; —O—S(═O)₂—NH(C₁₋₆-alkyl); —O—S(═O)₂—N(C₁₋₆-alkyl)₂; —NH₂;—NH(C₁₋₆-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—NH—C(═O)—O—C₁₋₆-alkyl; —NH—C(═O)—NH₂; —NH—C(═O)—NH(C₁₋₆-alkyl);—NH—C(═O)—N(C₁₋₆-alkyl)₂; —N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-C(═O)—NH₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O))₂OH;NH—S(═O))₂—C₁₋₆-alkyl; —NH—S(═O))₂—O—C₁₋₆-alkyl; —NH—S(═O)₂—NH₂;—NH—S(═O)₂—NH(C₁₋₆-alkyl); —NH—S(═O)₂N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-S(═O)₂—OH; —N(C₁₋₆-alkyl)-S(═O)₂—C₁₋₆-alkyl;—N(C₁₋₆alkyl)-S(═O)₂—O—C₁₋₆-alkyl; —N(C₁₋₆-alkyl)-S(═O)₂—NH₂;—N(C₁₋₆-alkyl)-S(═O)₂—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-S(═O)₂—N(C₁₋₄-alkyl)₂; —SCF₃; —SCF₂H; —SCFH₂;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₄-alkyl; —S(═O)₂—OH;—S(═O)₂—O—C₁₋₆-alkyl; S(═O)₂—NH₂; —S(═O)₂—NH(C₁₋₆-alkyl);—S(═O)₂—N(C₁₋₆-alkyl)₂; —C₃₋₆-cycloalkyl; 3 to 6-memberedheterocycloalkyl; phenyl; 5 or 6-membered heteroaryl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —O-phenyl;—O-(5 or 6-membered heteroaryl); —C(═O)—C₃₋₆-cycloalkyl; —C(═O)-(3 to6-membered heterocycloalkyl); —C(═O)-phenyl; —C(═O)-(5 or 6-memberedheteroaryl); —S(═O)₂—(C₃₋₆-cycloalkyl); —S(═O)₂-(3 to 6-memberedheterocycloalkyl); —S(═O)₂-phenyl or —S(═O)₂-(5 or 6-memberedheteroaryl); wherein aryl and 5 or 6-membered heteroaryl in each caseindependently from one another are unsubstituted or mono- orpolysubstituted with one or more substituents selected from —F; —Cl;—Br; —I; —CN; —C₁₋₆-alkyl; —CF₃; —CF₂H; —CFH₂; —CF₂Cl; —CFCl₂;—C₁₋₄-alkylene-CF₃; —C₁₋₄-alkylene-CF₂H; —C₁₋₄-alkylene-CFH₂;—C(═O)—C₁₋₆-alkyl; —C(═O)—OH; —C(═O)—OC₁₋₆-alkyl; —C(═O)—NH(OH);—C(═O)—NH₂; —C(═O)—NH(C₁₋₆-alkyl); —C(═O)—N(C₁₋₆-alkyl)₂; —OH; ═O;—OCF₃; —OCF₂H; —OCFH₂; —OCF₂Cl; —OCFCl₂; —O—C₁₋₆-alkyl;—O—C₃₋₆-cycloalkyl; —O-(3 to 6-membered heterocycloalkyl); —NH₂;—NH(C₁₋₄-alkyl); —N(C₁₋₆-alkyl)₂; —NH—C(═O)—C₁₋₆-alkyl;—N(C₁₋₆-alkyl)-C(═O)—C₁₋₆-alkyl; —NH—C(═O)—NH₂;—NH—C(═O)—NH(C₁₋₆-alkyl); —NH—C(═O)—N(C₁₋₆-alkyl)₂;—N(C₁₋₆-alkyl)-C(═O)—NH(C₁₋₆-alkyl);—N(C₁₋₆-alkyl)-C(═O)—N(C₁₋₆-alkyl)₂; —NH—S(═O)₂—C₁₋₆-alkyl; —SCF₃;—S—C₁₋₆-alkyl; —S(═O)—C₁₋₆-alkyl; —S(═O)₂—C₁₋₆-alkyl; —S(═O)₂—NH₂;—S(═O)₂—NH(C₁₋₆-alkyl); —S(═O)₂—N(C₁₋₄-alkyl)₂; —C₃₋₆-cycloalkyl;—C₁₋₄-alkylene-C₃₋₆-cycloalkyl; 3 to 6-membered heterocycloalkyl;—C₁₋₄-alkylene-(3 to 6-membered heterocycloalkyl); phenyl or 5 or6-membered heteroaryl; in the form of the free compound or aphysiologically acceptable salt thereof.
 2. The compound according toclaim 1, wherein X represents CR₅, Y represents CR₆; and Z representsCR₇; or X represents N, Y represents CR₆; and Z represents CR₇; or Xrepresents CR₅, Y represents N; and Z represents CR₇; or X representsCR₅, Y represents CR₆; and Z represents N; or X represents N, Yrepresents N; and Z represents CR₇; or X represents N, Y represents CR₆;and Z represents N; or X represents CR₅, Y represents N; and Zrepresents N; or X represents N, Y represents N; and Z represents N. 3.The compound according to claim 2, wherein optionally present R₅represents —H; optionally present R₆ represents —H; and/or optionallypresent R₇ represents —H
 4. The compound according to claim 1, whereinR₁ represents —C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl;or 5 or 6-membered heteroaryl.
 5. The compound according to claim 1,wherein R₂ represents —C(═O)—C₁₋₁₀-alkyl; —C(═O)—C₃₋₁₀-cycloalkyl;—C(═O)—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; —C(═O)-(3 to 7 memberedheterocycloalkyl); —C(═O)-(5 or 6-membered heteroaryl);—S(═O)₂—C₁₋₁₀-alkyl; —S(═O)₂—C₃₋₁₀-cycloalkyl;—S(═O)₂—C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; or —S(═O)₂-(5 or 6-memberedheteroaryl).
 6. The compound according to claim 1, wherein R₃ represents—C₁₋₁₀-alkyl; —C₃₋₁₀-cycloalkyl; —C₁₋₆-alkylene-C₃₋₁₀-cycloalkyl; aryl;—C₁₋₆-alkylene-aryl.
 7. The compound according to claim 1, wherein R₄represents —H.
 8. The compound according to claim 1, wherein R₁represents cyclopropyl, unsubstituted; —CH₂-cyclopropyl, unsubstituted;phenyl, unsubstituted or mono- or disubstituted with substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —CH₃, —CF₃, —CN, cyclopropyl and —OCH₃, wherein phenyl isoptionally annealed to a dioxolane ring by a substituent —O—CH₂CH₂—O—;or pyridyl, unsubstituted or mono- or disubstituted with substituentsindependently of one another selected from the group consisting of —F,—Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃.
 9. The compound according to claim1, wherein R₂ represents —C(═O)—C₁₋₁₀-alkyl, unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, and —Br; —C(═O)-cyclopropyl,unsubstituted or mono- or disubstituted with substituents independentlyof one another selected from the group consisting of —F, —Cl, —Br, —CH₃,—CF₃, —CN, and —OCH₃; —C(═O)-cyclobutyl, unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN and —OCH₃;—C(═O)-2-tetrahydrofuranyl, unsubstituted; —C(═O)-(5- to 6-memberedheteroaryl), wherein said 5- to 6-membered heteroaryl is selected fromthe group consisting of thiazolyl, pyrazolyl, oxazolyl and1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, whereinin each case said 5- to 6-membered heteroaryl is unsubstituted or mono-or disubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O, and—OCH₃; —S(═O)₂—C₁₋₁₀-alkyl, unsubstituted; —S(═O)₂-cyclopropyl,unsubstituted; —S(═O)₂—CH₂₋cyclopropyl, unsubstituted; or —S(═O)₂-(5- to6-membered heteroaryl), wherein said 5- to 6-membered heteroaryl isselected from the group consisting of thiazolyl, pyrazolyl, oxazolyl and1-oxa-2,4-diazolyl, 1,2,5-oxadiazolyl, isoxazolyl, isothiazolyl, whereinin each case said 5- to 6-membered heteroaryl is unsubstituted or mono-or disubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, ═O, and—OCH₃.
 10. The compound according to claim 1, wherein R₃ represents—C₁₋₁₀-alkyl, unsubstituted or mono- or disubstituted with substituentsindependently of one another selected from the group consisting of —F,—Cl, and —Br; cyclohexyl, unsubstituted or mono- or disubstituted withsubstituents independently of one another selected from the groupconsisting of —F, —Cl, and —Br; —CH₂-cyclopropyl, unsubstituted;—CH₂-cyclohexyl, unsubstituted or mono- or disubstituted withsubstituents independently of one another selected from the groupconsisting of —F, —Cl, and —Br; phenyl, unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃;or —CH₂-phenyl, unsubstituted or mono- or disubstituted withsubstituents independently of one another selected from the groupconsisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN, and —OCH₃.
 11. The compoundaccording to claim 1, wherein R₁ represents phenyl, unsubstituted ormono- or disubstituted with substituents independently of one anotherselected from the group consisting of —F, —Cl, —Br, —CH₃, —CF₃, —CN,cyclopropyl and —OCH₃; and/or R₂ represents —C(═O)—C₁₋₆-alkyl;—C(═O)-cyclopropyl; or —C(═O)-cyclobutyl, unsubstituted or mono- ordisubstituted with substituents independently of one another selectedfrom the group consisting of —F, —Cl, and —Br; and/or R₃ representsfluoro-phenyl.
 12. The compound according to claim 1, selected from thegroup consisting of 12,2-difluoro-N-[rac-(2R,3S)-2-(2,3-dihydro-1,4-benzodioxin-6-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide22,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide32,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide42,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]propanamide52,2-difluoro-N-[rac-(2R,3S)-2-(2,4-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide62,2-difluoro-N-[rac-(2R,3S)-1-[1-(3,4-difluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide72,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]propanamide8N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropane-carboxamide9N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropane-sulfonamide10N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide112,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide12N-[(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-2,2-difluoro-propanamide131-methyl-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide141-fluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide15N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide16N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide17N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl-]1-(trifluoromethyl)cyclopropanecarboxamide181-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide19N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide202,2-difluoro-N-[(2S,3R)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide212,2-difluoro-N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide221-methyl-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide231-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide242,2-difluoro-N-[(2S,3R)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide252,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide262,2-difluoro-N-[rac-(2R,3S)-2-(3,5-difluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide272,2-difluoro-N-[rac-(2R,3S)-5-oxo-2-phenyl-1-(1-phenylindazol-5-yl)pyrrolidin-3-yl]propanamide28N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclo-propanecarboxamide292,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide302,2-difluoro-N-[rac-(2R,3S)-1-[1-(3-cyanophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide312,2-difluoro-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide32N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclobutanecarboxamide332,2-difluoro-N-[(2R,3S)-2-(2-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide34N-[(2R,3S)-2-(4-fluoro-3-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide362,2-difluoro-N-[rac-(2S,3S)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide371-cyclopropyl-N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]methanesulfonamide382,2-difluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide39N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide422,2-difluoro-N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide43N-[(2S,3R)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide45 1:1 mixture of (1S,2S)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamideand (1S,2S)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide46 rac-(1S,2R)-2-fluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide482,2-difluoro-N-[rac-(2S,3R)-2-cyclopropyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide49N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(2-methoxy-4-pyridyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide51N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanesulfonamide522-methyl-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide53N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide54N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide55N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide56 1:1 mixture of(1R,2R)-2-fluoro-N-[(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamideand(1R,2R)-2-fluoro-N-[(2S,3R)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide61N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide62N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide63 1:1 mixture of(1R,2R)-2-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamideand(1R,2R)-2-fluoro-N-[(2S,3R)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(3-methoxyphenyl)-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide65N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide66N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]acetamide67N-[rac-(2R,3S)-2-(3-chlorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide682,2-difluoro-N-[rac-(2R,3S)-2-(3-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide692,2-difluoro-N-[(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide701-fluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]cyclopropanecarboxamide71N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-pyrrolidin-3-yl]-1-(trifluoromethyl)cyclopropanecarboxamide722,2-difluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-2-(o-tolyl)-5-oxo-pyrrolidin-3-yl]propanamide731-fluoro-N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]cyclopropanecarboxamide74N-[(2R,3S)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]-1-methyl-cyclopropanecarboxamide752,2-difluoro-N-[rac-(2R,3S)-1-[1-(4,4-difluorocyclohexyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide762,2-difluoro-N-[rac-(2R,3S)-1-(1-cyclohexylindazol-5-yl)-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide772,2-difluoro-N-[rac-(2R,3S)-2-(2-fluoro-5-methoxy-phenyl)-1-(1-methylindazol-5-yl)-5-oxo-pyrrolidin-3-yl]propanamide782,2-difluoro-N-[rac-(2R,3S)-1-[1-(2,2-difluoroethyl)indazol-5-yl]-2-(2-fluoro-5-methoxy-phenyl)-5-oxo-pyrrolidin-3-yl]propanamide792,2-difluoro-N-[rac-(2R,3S)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide802,2-difluoro-N-[rac-(2R,3S)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide812,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide822,2-difluoro-N-[rac-(2R,3S)-1-[1-(cyclopropylmethyl)indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide842,2-difluoro-N-[rac-(2R,3S)-1-[1-[(4,4-difluorocyclohexyl)methyl]indazol-5-yl]-5-oxo-2-phenyl-pyrrolidin-3-yl]propanamide852,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(2-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide862,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(4-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide872,2-difluoro-N-[rac-(2R,3S)-2-(4-fluorophenyl)-1-[1-[(3-fluorophenyl)methyl]indazol-5-yl]-5-oxo-pyrrolidin-3-yl]propanamide88N-[(2R,3S)-2-benzyl-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxopyrrolidin-3-yl]-2,2-difluoropropanamide892,2-difluoro-N-[rac-(2R,3S)-2-ethyl-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide902,2-difluoro-N-[rac-(2R,3R)-2-(cyclopropylmethyl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]propanamide912-cyclopropyl-N-[(2S,3R)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]acetamide92N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1-methyl-1H-pyrazole-3-carboxamide93N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-1H-imidazole-2-carboxamide94N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-2-methyloxazole-5-carboxamide95N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]-5-methylthiazole-4-carboxamide96N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]pyrimidine-2-carboxamide97N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]nicotinamide98N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]oxetane-3-carboxamide99N-[(2R,3S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-5-oxo-2-phenylpyrrolidin-3-yl]thiazole-5-sulfonamide100N-[rac-(2R,3R)-2-(5-chlorothiophen-2-yl)-1-[1-(4-fluorophenyl)indazol-5-yl]-5-oxopyrrolidin-3-yl]cyclopropanesulfonamide1012,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide1022,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[3,4-c]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamide1032,2-difluoro-N-[rac-(2R,3S)-1-[1-(4-fluorophenyl)pyrazolo[4,3-b]pyridin-5-yl]-5-oxo-2-phenylpyrrolidin-3-yl]propanamidein each case in the form of the free compound or a physiologicallyacceptable salt thereof.
 13. A pharmaceutical dosage form comprising acompound according to claim
 1. 14. A method for treatment and/orprophylaxis of pain and/or inflammations in a subject, comprising a stepof administering the subject a compound according to claim
 1. 15. Themethod according to claim 14 for the treatment and/or prophylaxis ofasthma, rheumatoid arthritis, inflammatory bowel disease, chronicobstructive pulmonary disease, acute respiratory distress syndrome,cystic fibrosis, osteoarthritis, polymyalgia rheumatica, giant cellarteritis, Sjögren syndrome, Duchenne muscular dystrophy, vasculitis,Behçet's disease, ulcerative colitis and/or Crohn's disease.